Thienopyrazine inhibitors of irak4 activity

ABSTRACT

The present invention relates to thienopyrazine inhibitors of IRAK4 of formula (I) and provides compositions comprising such inhibitors, as well as methods therewith for treating IRAK4-mediated or -associated conditions or diseases.

BACKGROUND OF THE INVENTION

The present invention is directed to compounds which modulateinterleukin-1 (IL-1) receptor-associated kinase 4 (IRAK4) and are usefulin the prevention or treatment of inflammatory, cell proliferative andimmune-related conditions and diseases.

The recruitment of immune cells to sites of injury involves theconcerted interactions of a large number of soluble mediators. Severalcytokines appear to play key roles in these processes, particularly IL-1and TNF. Both cytokines are derived from mononuclear cells andmacrophages, along with other cell types. Physiologically, they producemany of the same proinflammatory responses, including fever, sleep andanorexia, mobilization and activation of polymorphonuclear leukocytes,induction of cyclooxygenase and lipoxygenase enzymes, increase inadhesion molecule expression, activation of B-cells, T-cells and naturalkiller cells, and stimulation of production of other cytokines. Otheractions include a contribution to the tissue degeneration observed inchronic inflammatory conditions, such as stimulation of fibroblastproliferation, induction of collagenase, etc. They have also beenimplicated in the process of bone resorption and adipose tissueregulation. Thus, these cytokines play key roles in a large number ofpathological conditions, including rheumatoid arthritis, inflammatorybowel disease, multiple sclerosis, diabetes, obesity, cancer, sepsis,etc.

The importance of IL-1 in inflammation has been demonstrated by theability of the highly specific IL-1 receptor antagonist protein (IL-1Raor IRAP) to relieve inflammatory conditions. See, e.g., Dinarello,Cytokine Growth Factor Rev., 1997, 8:253-265.

IL-1 treatment of cells induces the formation of a complex consisting ofthe two IL-1 receptor chains, IL-1R1 and IL-1RAcP, and the resultingheterodimer recruits an adaptor molecule designated as MyD88. See e.g.,Wesche et al., J. Biol. Chem., 1999, 274:19403-19410. MyD88 binds to aprotein designated IRAK (IL-1 receptor associated kinase). See, e.g.,O'Neill et al., J. Leukoc. Biol., 1998, 63(6):650-657; Auron, CytokineGrowth Factor Rev., 1998, 9(3-4):221-237; and O'Neill, Biochem. Soc.Trans., 2000, 28(5):557-563. IRAK is subsequently phosphorylated andreleased from the receptor complex to interact with a tumor necrosisfactor receptor-associated factor, TRAF6, which transduces the signal todownstream effector molecules. See e.g., Cao et al., Nature, 1996,383:443-446. TRAF6 can trigger the NIK/IKK kinase cascade to activatethe transcription factor NK-kappa B. NF-kappa B regulates a number ofgenes that, in turn, regulate immune and inflammatory responses.

Four IRAKs have been identified: IRAK1 (see, e.g., Cao et al., Science,1996, 271:1128-1131), IRAK2 (see, e.g. Muzio et al., Science, 1997,278:1612-1615), the monomyeloic cell specific IRAKM, also known as IRAK3(see, e.g., Wesche et al., J. Biol. Chem., 1999, 274:19403-19410), andIRAK4 (see, e.g., PCT Publication No. WO 01/051641). IRAK proteins havebeen shown to play a role in transducing signals other than thoseoriginating from IL-1 receptors, including signals triggered byactivation of IL-18 receptors (see, e.g., Kanakaraj et al., J. Exp.Med., 1999, 189(7):1129-1138) and LPS receptors (see, e.g., Yang et al.,J. Immunol., 1999, 163:639-643; and Wesche et al., J. Biol. Chem., 1999,274:19403-19410). Over-expression of IRAK2 and IRAKM has been shown tobe capable of reconstituting the response to IL-1 and LPS in an IRAKdeficient cell line.

The identification of compounds that inhibit the function of IRAK4represents an attractive approach to the development of therapeuticagents for the treatment of inflammatory, cell proliferative andimmune-related conditions and diseases associated with IRAK4-mediatedsignal transduction, such as rheumatoid arthritis, inflammatory boweldisease, multiple sclerosis, diabetes, obesity, allergic disease,psoriasis, asthma, graft rejection, cancer, and sepsis.

It is an object of the instant invention to provide novel compounds thatare inhibitors of IRAK4.

It is also an object of the present invention to provide pharmaceuticalcompositions that comprise the novel compounds that are inhibitors ofIRAK4.

It is also an object of the present invention to provide a method fortreating IRAK4-mediated and associated conditions or diseases thatcomprises administering such inhibitors of IRAK4 activity.

SUMMARY OF THE INVENTION

The present invention relates to thienopyrazine inhibitors of IRAK4 offormula (I) and provides compositions comprising such inhibitors, aswell as methods therewith for treating IRAK4-mediated or -associatedconditions or diseases.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the instant invention are useful in the inhibition ofthe activity of IRAK4.

An embodiment of the instant invention is illustrated by the Formula I:

wherein:

Ring A is aryl or heterocyclyl;

n is 0, 1, 2, 3 or 4;

R₁ is independently selected from: (C₁-C₄)alkyl, (C₃-C₆)cycloalkyl,heterocyclyl, CF₃, CHF₂, CN, halo, said alkyl, cycloalkyl andheterocyclyl optionally substituted with halo, OH, CH₃, and OCH₃;

R₂ is H and R₃ is independently selected from: (C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, and heterocyclyl each optionally substituted with oneor more halo, OH, N(R_(b))₂, or morpholinyl, or R₂ and R₃ can be takentogether with the nitrogen to which they are attached to form aheterocyclyl, said heterocyclyl optionally substituted with one or moresubstituents selected from R_(a);

R_(a) is independently selected from (C₁-C₄)alkyl, (C₃-C₆)cycloalkyl,CF₃, CHF₂, OH, halo and NH₂, said alkyl optionally substituted with(C₃-C₆)cycloalkyl and CF₃; and

R_(b) is independently selected from H and (C₁-C₄)alkyl;

or a pharmaceutically acceptable salt thereof.

Another embodiment of the instant invention is illustrated by theFormula I:

wherein:

Ring A is pyrazolyl, pyridinyl, thiophenyl, furanyl or phenyl;

n is 0, 1 or 2;

R₁ is independently selected from: (C₁-C₄)alkyl, cyclopropyl,oxadiazolyl, pyridinyl, oxazolyl, triazolyl, pyriminidyl, CF₃, CHF₂, CNand halo, said alkyl, oxadiazolyl, pyridinyl, oxazolyl, triazolyl andpyriminidyl are optionally substituted with halo, OH, CH₃, and OCH₃;

R₂ is H and R₃ is independently selected from: (C₁-C₄)alkyl, cyclohexyl,cycloheptyl, piperidinyl and azepanyl each optionally substituted withone or more F, OH, N(R_(b))₂, or morpholinyl, or R₂ and R₃ can be takentogether with the nitrogen to which they are attached to form aheterocyclyl selected from piperazinyl, diazepanyl, diazabicyclooctyl,diazabicycloheptyl, diazaspirononyl, hexahydropyrrolopyrazinyl,piperidinyl, diazabicyclononyl, oxadiazabicyclodecyl anddiazatricyclodecyl, said heterocyclyl optionally substituted with one ormore substituents selected from R_(a);

R_(a) is independently selected from (C₁-C₄)alkyl, cyclopropyl, CF₃,CHF₂, OH, F and NH₂, said alkyl optionally substituted with cyclopropyland CF₃; and

R_(b) is independently selected from H and methyl;

or a pharmaceutically acceptable salt thereof.

A compound selected from:

-   2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-piperazin-1-ylthieno[2,3-b]pyrazine-7-carboxamide;-   2-{[(1R,2S)-2-hydroxycyclohexyl]amino}-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-[(3R)-piperidin-3-ylamino]thieno[2,3-b]pyrazine-7-carboxamide;-   2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   2-(1,4-diazepan-1-yl)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   2-(2,5-diazabicyclo[2.2.2]oct-2-yl)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   2-(5,8-diazaspiro[2.6]non-5-yl)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   2-[(3R)-3-aminopiperidin-1-yl]-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]-2-{[(1R,2S)-2-hydroxycyclohexyl]amino}thieno[2,3-b]pyrazine-7-carboxamide;-   2-(2,5-diazabicyclo[2.2.2]oct-2-yl)-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]-2-piperazin-1-ylthieno[2,3-b]pyrazine-7-carboxamide;-   2-(5,8-diazaspiro[2.6]non-5-yl)-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   2-(1,4-diazepan-1-yl)-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   2-(azepan-3-ylamino)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   N-(3-chloro-1-methyl-1H-pyrazol-4-yl)-2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   N-(3-chloro-1-methyl-1H-pyrazol-4-yl)-2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   N-(3-chloro-1-methyl-1H-pyrazol-4-yl)-2-(1,4-diazepan-1-yl)thieno[2,3-b]pyrazine-7-carboxamide;-   N-(3-bromo-1-methyl-1H-pyrazol-4-yl)-2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   N-(3-bromo-1-methyl-1H-pyrazol-4-yl)-2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   N-(3-bromo-1-methyl-1H-pyrazol-4-yl)-2-(1,4-diazepan-1-yl)thieno[2,3-b]pyrazine-7-carboxamide;-   2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   2-[(3R)-3-aminopiperidin-1-yl]-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   N-(3-cyano-1-methyl-1H-pyrazol-4-yl)-2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   N-(3-cyano-1-methyl-1H-pyrazol-4-yl)-2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   N-(3-cyano-1-methyl-1H-pyrazol-4-yl)-2-(1,4-diazepan-1-yl)thieno[2,3-b]pyrazine-7-carboxamide;-   2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-(3-bromo-1-methyl-1H-pyrazol-4-yl)thieno[2,3-b]pyrazine-7-carboxamide;-   2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(3-bromo-1-methyl-1H-pyrazol-4-yl)thieno[2,3-b]pyrazine-7-carboxamide;-   2-[(3S)-azepan-3-ylamino]-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]-2-[(3R)-piperidin-3-ylamino]thieno[2,3-b]pyrazine-7-carboxamide;-   2-[(3R)-azepan-3-ylamino]-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   2-[(3S)-azepan-3-ylamino]-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(3-chloro-1-methyl-1H-pyrazol-4-yl)thieno[2,3-b]pyrazine-7-carboxamide;-   2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-(3-cyano-1-methyl-1H-pyrazol-4-yl)thieno[2,3-b]pyrazine-7-carboxamide;-   2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(3-cyano-1-methyl-1H-pyrazol-4-yl)thieno[2,3-b]pyrazine-7-carboxamide;-   2-[(3R)-azepan-3-ylamino]-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   2-(3,8-diazabicyclo[3.2.1]oct-3-yl)-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   2-(3,8-diazabicyclo[3.2.1]oct-3-yl)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-(3-chloro-1-methyl-1H-pyrazol-4-yl)thieno[2,3-b]pyrazine-7-carboxamide;-   2-(3,8-diazabicyclo[3.2.1]oct-8-yl)-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   2-(3,8-diazabicyclo[3.2.1]oct-8-yl)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   N-(4-bromothiophen-3-yl)-2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   2-(1,4-diazepan-1-yl)-N-[4-(difluoromethyl)thiophen-3-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   N-(4-bromothiophen-3-yl)-2-(1,4-diazepan-1-yl)thieno[2,3-b]pyrazine-7-carboxamide;-   N-(4-bromothiophen-3-yl)-2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-[4-(difluoromethyl)thiophen-3-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   N-(2-bromothiophen-3-yl)-2-(1,4-diazepan-1-yl)thieno[2,3-b]pyrazine-7-carboxamide;-   N-(2-chlorothiophen-3-yl)-2-(1,4-diazepan-1-yl)thieno[2,3-b]pyrazine-7-carboxamide;-   2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(4-bromothiophen-3-yl)thieno[2,3-b]pyrazine-7-carboxamide;-   2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(2-bromothiophen-3-yl)thieno[2,3-b]pyrazine-7-carboxamide;-   N-(4-cyanothiophen-3-yl)-2-(1,4-diazepan-1-yl)thieno[2,3-b]pyrazine-7-carboxamide;-   2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(2-chlorothiophen-3-yl)thieno[2,3-b]pyrazine-7-carboxamide;-   2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(4-cyanothiophen-3-yl)thieno[2,3-b]pyrazine-7-carboxamide;-   2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]-N-[4-(difluoromethyl)thiophen-3-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]-N-[4-(difluoromethyl)thiophen-3-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-(2-chlorothiophen-3-yl)thieno[2,3-b]pyrazine-7-carboxamide;-   N-(2-chlorothiophen-3-yl)-2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   N-(2-chlorothiophen-3-yl)-2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   N-(2-bromothiophen-3-yl)-2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   N-(2-bromothiophen-3-yl)-2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   N-(4-cyanothiophen-3-yl)-2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   N-(4-cyanothiophen-3-yl)-2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-[4-(difluoromethyl)thiophen-3-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-(4-bromothiophen-3-yl)thieno[2,3-b]pyrazine-7-carboxamide;-   N-(2-cyanothiophen-3-yl)-2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   N-(2-cyanothiophen-3-yl)-2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-(2-bromothiophen-3-yl)thieno[2,3-b]pyrazine-7-carboxamide;-   N-(2-cyanothiophen-3-yl)-2-(1,4-diazepan-1-yl)thieno[2,3-b]pyrazine-7-carboxamide;-   2-(1,4-diazepan-1-yl)-N-[2-(trifluoromethyl)thiophen-3-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]-N-[2-(trifluoromethyl)thiophen-3-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]-N-[2-(trifluoromethyl)thiophen-3-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-[2-(trifluoromethyl)thiophen-3-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(2-cyanothiophen-3-yl)thieno[2,3-b]pyrazine-7-carboxamide;-   2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-(2-cyanothiophen-3-yl)thieno[2,3-b]pyrazine-7-carboxamide;-   2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-(4-cyanothiophen-3-yl)thieno[2,3-b]pyrazine-7-carboxamide;-   N-(2-cyanophenyl)-2-(1,4-diazepan-1-yl)thieno[2,3-b]pyrazine-7-carboxamide;-   2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-[2-(trifluoromethyl)phenyl]thieno[2,3-b]pyrazine-7-carboxamide;-   N-(2-bromophenyl)-2-(1,4-diazepan-1-yl)thieno[2,3-b]pyrazine-7-carboxamide;-   N-(2-cyanophenyl)-2-(5,8-diazaspiro[2.6]non-5-yl)thieno[2,3-b]pyrazine-7-carboxamide;-   2-[(3R)-3-aminopiperidin-1-yl]-N-(2-cyanophenyl)thieno[2,3-b]pyrazine-7-carboxamide;-   N-(2-cyanophenyl)-2-[(3R)-piperidin-3-ylamino]thieno[2,3-b]pyrazine-7-carboxamide;-   N-(2-cyanophenyl)-2-piperazin-1-ylthieno[2,3-b]pyrazine-7-carboxamide;-   2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(2-bromophenyl)thieno[2,3-b]pyrazine-7-carboxamide;-   N-(2-bromophenyl)-2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   N-(2-bromophenyl)-2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   2-(1,4-diazepan-1-yl)-N-[2-(trifluoromethyl)phenyl]thieno[2,3-b]pyrazine-7-carboxamide;-   N-(2-chlorophenyl)-2-(1,4-diazepan-1-yl)thieno[2,3-b]pyrazine-7-carboxamide;-   2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(2-chlorophenyl)thieno[2,3-b]pyrazine-7-carboxamide;-   2-[(3    S)-azepan-3-ylamino]-N-(2-cyanophenyl)thieno[2,3-b]pyrazine-7-carboxamide;-   2-[(3R)-azepan-3-ylamino]-N-(2-cyanophenyl)thieno[2,3-b]pyrazine-7-carboxamide;-   2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(2-cyanophenyl)thieno[2,3-b]pyrazine-7-carboxamide;-   2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-(2-bromophenyl)thieno[2,3-b]pyrazine-7-carboxamide;-   N-(2-cyanophenyl)-2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   N-(2-cyanophenyl)-2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   N-(2-chlorophenyl)-2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   N-(2-chlorophenyl)-2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-(2-chlorophenyl)thieno[2,3-b]pyrazine-7-carboxamide;-   2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-[2-(difluoromethyl)phenyl]thieno[2,3-b]pyrazine-7-carboxamide;-   2-(1,4-diazepan-1-yl)-N-[2-(difluoromethyl)phenyl]thieno[2,3-b]pyrazine-7-carboxamide;-   2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]-N-[2-(difluoromethyl)phenyl]thieno[2,3-b]pyrazine-7-carboxamide;-   2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-(2-cyanophenyl)thieno[2,3-b]pyrazine-7-carboxamide;-   2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-[2-(difluoromethyl)phenyl]thieno[2,3-b]pyrazine-7-carboxamide;-   N-(4-chlorothiophen-3-yl)-2-(1,4-diazepan-1-yl)thieno[2,3-b]pyrazine-7-carboxamide;-   N-(4-chlorothiophen-3-yl)-2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   N-(4-chlorothiophen-3-yl)-2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;-   2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(4-chlorothiophen-3-yl)thieno[2,3-b]pyrazine-7-carboxamide;    and-   2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-(4-chlorothiophen-3-yl)thieno[2,3-b]pyrazine-7-carboxamide;-   or a pharmaceutically acceptable salt thereof.

When any variable (e.g. R_(a), etc.) occurs more than one time in anyconstituent, its definition on each occurrence is independent at everyother occurrence. Also, combinations of substituents and variables arepermissible only if such combinations result in stable compounds.

Lines drawn into the ring systems from substituents represent that theindicated bond may be attached to any of the substitutable ring atoms.If the ring system is bicyclic, it is intended that the bond be attachedto any of the suitable atoms on either ring of the bicyclic moiety.

It is understood that one or more silicon (Si) atoms can be incorporatedinto the compounds of the instant invention in place of one or morecarbon atoms by one of ordinary skill in the art to provide compoundsthat are chemically stable and that can be readily synthesized bytechniques known in the art from readily available starting materials.Carbon and silicon differ in their covalent radius leading todifferences in bond distance and the steric arrangement when comparinganalogous C-element and Si-element bonds. These differences lead tosubtle changes in the size and shape of silicon-containing compoundswhen compared to carbon. One of ordinary skill in the art wouldunderstand that size and shape differences can lead to subtle ordramatic changes in potency, solubility, lack of off target activity,packaging properties, and so on. (Diass, J. O. et al. Organometallics(2006) 5:1188-1198; Showell, G. A. et al. Bioorganic & MedicinalChemistry Letters (2006) 16:2555-2558).

It is understood that substituents and substitution patterns on thecompounds of the instant invention can be selected by one of ordinaryskill in the art to provide compounds that are chemically stable andthat can be readily synthesized by techniques known in the art, as wellas those methods set forth below, from readily available startingmaterials. If a substituent is itself substituted with more than onegroup, it is understood that these multiple groups may be on the samecarbon or on different carbons, so long as a stable structure results.In some instances, two substituents are attached to the same carbon andcome together to form a carbocyclic or heterocyclic ring (a spirocyclicring system).

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. For example, C₁-C₆, as in“(C₁-C₆)alkyl” is defined to include groups having 1, 2, 3, 4, 5 or 6carbons in a linear or branched arrangement. For example, “(C₁-C₆)alkyl”specifically includes methyl, ethyl, n-propyl, i-propyl, n-butyl,t-butyl, i-butyl, pentyl, hexyl, and so on. For example, C₁-C₄, as in“(C₁-C₄)alkyl” is defined to include groups having 1, 2, 3 or 4 carbonsin a linear or branched arrangement. For example, “(C₁-C₄)alkyl”specifically includes methyl, ethyl, n-propyl, i-propyl, n-butyl,t-butyl and i-butyl.

The term “cycloalkyl” means a monocyclic saturated aliphatic hydrocarbongroup having the specified number of carbon atoms. For example,“cycloalkyl” includes cyclopropyl, methyl-cyclopropyl,2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, and so on.

As used herein, “aryl” is intended to mean any stable monocyclic orbicyclic carbon ring of up to 7 atoms in each ring, wherein at least onering is aromatic. Examples of such aryl elements include phenyl,naphthyl, tetrahydro-naphthyl, indanyl and biphenyl. In cases where thearyl substituent is bicyclic and one ring is non-aromatic, it isunderstood that attachment is via the aromatic ring.

The term “heterocycle” or “heterocyclyl” as used herein is intended tomean a 3- to 10-membered aromatic or nonaromatic heterocycle containingfrom 1 to 4 heteroatoms selected from the group consisting of O, N andS, and includes spiro, bicyclic and tricyclic groups. “Heterocyclyl”therefore includes heteroaryls, as well as dihydro and tetrathydroanalogs thereof. Further examples of “heterocyclyl” include, but are notlimited to the following: benzoimidazolyl, benzoimidazolonyl,benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl,benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl,furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl,isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl,naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline,oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl,pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl,quinoxalinyl, tetrahydropyranyl, tetrazolyl, tetrazolopyridyl,thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl,hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl,pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl,dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl,dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl,dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, andN-oxides thereof. Attachment of a heterocyclyl substituent can occur viaa carbon atom or via a heteroatom.

As appreciated by those of skill in the art, “halo” or “halogen” as usedherein is intended to include chloro (Cl), fluoro (F), bromo (Br) andiodo (I).

The compounds of this invention include the salts, solvates, hydrates orprodrugs of the compounds. The use of the terms “salt”, “solvate”,“hydrate”, “prodrug” and the like, is intended to equally apply to thesalt, solvate, hydrate and prodrug of enantiomers, stereoisomers,rotamers, tautomers, positional isomers, or racemates of the inventivecompounds.

Salts

The IRAK4 inhibitor compounds of the present invention, which can be inthe form of a free base, may be isolated from the reaction mixture inthe form of a pharmaceutically acceptable salt.

The compounds of Formula I can form salts which are also within thescope of this invention. Reference to a compound of Formula I herein isunderstood to include reference to pharmaceutically acceptable saltsthereof, unless otherwise indicated. The term “pharmaceuticallyacceptable salt(s)” or “salt”, as employed herein, denotes acidic saltsformed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases. In addition, when a compoundof Formula I contains both a basic moiety, such as, but not limited to apyridine or imidazole, and an acidic moiety, such as, but not limited toa carboxylic acid, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Such acidic and basicsalts used within the scope of the invention are pharmaceuticallyacceptable (i.e., non-toxic, physiologically acceptable) salts. Salts ofthe compounds of Formula I may be formed, for example, by reacting acompound of Formula I with an amount of acid or base, such as anequivalent amount, in a medium such as one in which the saltprecipitates or in an aqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates,) and the like. Additionally,acids which are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds arediscussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook ofPharmaceutical Salts. Properties, Selection and Use. (2002) Zurich:Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977)66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996),Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g., decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g., benzyl andphenethyl bromides), and others.

Crystals

The IRAK4 inhibitor compounds of the present invention may exist asamorphous forms or crystalline forms.

The compounds of Formula I may have the ability to crystallize in morethan one form, a characteristic known as polymorphism, and it isunderstood that such polymorphic forms (“polymorphs”) are within thescope of Formula I. Polymorphism generally can occur as a response tochanges in temperature or pressure or both and can also result fromvariations in the crystallization process. Polymorphs can bedistinguished by various physical characteristics known in the art suchas x-ray diffraction patterns, solubility and melting point.

Solvates

The compounds having Formula I or the pharmaceutically acceptable saltsmay form hydrates or solvates. It is known to those of skill in the artthat charged compounds form hydrated species when lyophilized withwater, or form solvated species when concentrated in a solution with anappropriate organic solvent. The compounds of this invention include thehydrates or solvates of the compounds listed.

One or more compounds of the invention having Formula I or thepharmaceutically acceptable salts or solvates thereof may exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like, and it is intended thatthe invention embrace both solvated and unsolvated forms. “Solvate”means a physical association of a compound of this invention with one ormore solvent molecules. This physical association involves varyingdegrees of ionic and covalent bonding, including hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolatable solvates. Non-limiting examples ofsuitable solvates include ethanolates, methanolates, and the like.“Hydrate” is a solvate wherein the solvent molecule is H₂O.

Preparation of solvates is generally known. Thus, for example, M. Cairaet al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describe thepreparation of the solvates of the antifungal fluconazole in ethylacetate as well as from water. Similar preparations of solvates,hemisolvate, hydrates and the like are described by E. C. van Tonder etal, AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham etal, Chem. Commun. 603-604 (2001). A typical, non-limiting, processinvolves dissolving the inventive compound in desired amounts of thedesired solvent (organic or water or mixtures thereof) at a higher thanambient temperature, and cooling the solution at a rate sufficient toform crystals which are then isolated by standard methods. Analyticaltechniques such as, for example IR spectroscopy, show the presence ofthe solvent (or water) in the crystals as a solvate (or hydrate).

Optical Isomers

The compounds of Formula I may contain asymmetric or chiral centers,and, therefore, exist in different stereoisomeric forms. It is intendedthat all stereoisomeric forms of the compounds of Formula I, as well asmixtures thereof, including racemic mixtures, form part of the presentinvention. In addition, the present invention embraces all geometric andpositional isomers. For example, if a compound of Formula I incorporatesa double bond or a fused ring, both the cis- and trans-forms, as well asmixtures, are embraced within the scope of the invention. Suchstereoisomeric forms also include enantiomers and diastereoisomers, etc.

For chiral compounds, methods for asymmetric synthesis whereby the purestereoisomers are obtained are well known in the art, e.g. synthesiswith chiral induction, synthesis starting from chiral intermediates,enantioselective enzymatic conversions, separation of stereoisomersusing chromatography on chiral media. Such methods are described inChirality in Industry (edited by A. N. Collins, G. N. Sheldrake and J.Crosby, 1992; John Wiley). Likewise methods for synthesis of geometricalisomers are also well known in the art.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g. hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers. Also,some of the compounds of Formula I may be atropisomers (e.g. substitutedbiaryls) and are considered as part of this invention. Enantiomers canalso be separated by use of chiral HPLC column.

It is also possible that the compounds of Formula I may exist indifferent tautomeric forms, and all such forms are embraced within thescope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates, esters and prodrugs of the compounds as well as the salts,solvates and esters of the prodrugs), such as those which may exist dueto asymmetric carbons on various substituents, including enantiomericforms (which may exist even in the absence of asymmetric carbons),rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this invention, as are positionalisomers. Individual stereoisomers of the compounds of the invention may,for example, be substantially free of other isomers, or may be admixed,for example, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, isintended to equally apply to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or prodrugs of the inventive compounds.

Prodrugs

A discussion of prodrugs is provided in T. Higuchi and V. Stella,Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. SymposiumSeries, and in Bioreversible Carriers in Drug Design, (1987) Edward B.Roche, ed., American Pharmaceutical Association and Pergamon Press. Theterm “prodrug” means a compound (e.g, a drug precursor) that istransformed in vivo to yield a compound of Formula I or apharmaceutically acceptable salt, hydrate or solvate of the compound.The transformation may occur by various mechanisms (e.g. by metabolic orchemical processes), such as, for example, through hydrolysis in blood.A discussion of the use of prodrugs is provided by T. Higuchi and W.Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S.Symposium Series, and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987.

Isotopes

In the compounds of Formula I, the atoms may exhibit their naturalisotopic abundances, or one or more of the atoms may be artificiallyenriched in a particular isotope having the same atomic number, but anatomic mass or mass number different from the atomic mass or mass numberpredominantly found in nature. The present invention is meant to includeall suitable isotopic variations of the compounds of generic Formula I.For example, different isotopic forms of hydrogen (H) include protium(¹H) and deuterium (²H). Protium is the predominant hydrogen isotopefound in nature. Enriching for deuterium may afford certain therapeuticadvantages, such as increasing in vivo half-life or reducing dosagerequirements, or may provide a compound useful as a standard forcharacterization of biological samples. Isotopically-enriched compoundswithin generic Formula I can be prepared without undue experimentationby conventional techniques well known to those skilled in the art or byprocesses analogous to those described in the Schemes and Examplesherein using appropriate isotopically-enriched reagents and/orintermediates.

Certain isotopically-labelled compounds of Formula I (e.g. those labeledwith ³H and ¹⁴C) are useful in compound and/or substrate tissuedistribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C)isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labelled compounds of Formula I cangenerally be prepared by following procedures analogous to thosedisclosed in the Schemes and/or in the Examples herinbelow, bysubstituting an appropriate isotopically labeled reagent for anon-isotopically labeled reagent.

Utility

According to another embodiment, the present invention provides a methodof treating or reducing the severity of a disease in a patient by usinga compound of Formulas I as described above, wherein said disease isselected from IRAK4 mediated pathologies, such as rheumatoid arthritis,multiple sclerosis, sepsis, osteoarthritis, inflammatory bowel disease,Parkinson's disease, cardiac contractile dysfunction, type I diabetes,type II diabetes or familial cold autoinflammatory syndrome, allergicdisease, cancer, lupus, psoriasis, asthma or graft rejection.

The compounds of the invention find use in a variety of applications. Aswill be appreciated by those skilled in the art, the kinase activity ofIRAK4 may be modulated in a variety of ways; that is, one can affect thephosphorylation/activation of IRAK4 either by modulating the initialphosphorylation of the protein or by modulating the autophosphorylationof the other active sites of the protein. Alternatively, the kinaseactivity of IRAK4 may be modulated by affecting the binding of asubstrate of IRAK4 phosphorylation.

The compounds of the invention are used to treat or prevent inflammationrelated diseases. Disease states which can be treated by the methods andcompositions provided herein include, but are not limited to, cancer,autoimmune disease, viral disease, fungal disease,neurological/neurodegenerative disorders, arthritis, inflammation,anti-proliferative (e.g. ocular retinopathy), neuronal, alopecia,cardiovascular disease, graft rejection, inflammatory bowel disease,proliferation induced after medical procedures, including, but notlimited to, surgery, angioplasty, and the like. It is appreciated thatin some cases the cells may not be in a hyper- or hypoproliferationstate (abnormal state) and still require treatment. Thus, in oneembodiment, the invention herein includes application to cells orindividuals which are afflicted or may eventually become afflicted withany one of these disorders or states.

The compounds of this invention may be administered to mammals,including humans, either alone or, in combination with pharmaceuticallyacceptable carriers, excipients or diluents, in a pharmaceuticalcomposition, according to standard pharmaceutical practice. Thecompounds can be administered orally or parenterally, including theintravenous, intramuscular, intraperitoneal, subcutaneous and topicalroutes of administration.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, microcrystalline cellulose, sodiumcrosscarmellose, corn starch, or alginic acid; binding agents, forexample starch, gelatin, polyvinyl-pyrrolidone or acacia, andlubricating agents, for example, magnesium stearate, stearic acid ortalc. The tablets may be uncoated or they may be coated by knowntechniques to mask the unpleasant taste of the drug or delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a watersoluble taste masking material such as hydroxypropylmethyl-cellulose orhydroxypropylcellulose, or a time delay material such as ethylcellulose, cellulose acetate buryrate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with watersoluble carrier such as polyethyleneglycol or an oil medium, for examplepeanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethylene-oxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present. These compositions may be preserved by theaddition of an anti-oxidant such as ascorbic acid.

The pharmaceutical compositions of the invention may also be in the formof an oil-in-water emulsion. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring phosphatides, for example soy bean lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavouring agents, preservatives and antioxidants.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, flavoring and coloring agentsand antioxidant.

The pharmaceutical compositions may be in the form of sterile injectableaqueous solutions. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution and isotonic sodium chloridesolution.

The sterile injectable preparation may also be a sterile injectableoil-in-water microemulsion where the active ingredient is dissolved inthe oily phase. For example, the active ingredient may be firstdissolved in a mixture of soybean oil and lecithin. The oil solutionthen introduced into a water and glycerol mixture and processed to forma microemulsion.

The injectable solutions or microemulsions may be introduced into apatient's blood-stream by local bolus injection. Alternatively, it maybe advantageous to administer the solution or microemulsion in such away as to maintain a constant circulating concentration of the instantcompound. In order to maintain such a constant concentration, acontinuous intravenous delivery device may be utilized. An example ofsuch a device is the Deltec CADD-PLUS™ model 5400 intravenous pump.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension for intramuscular andsubcutaneous administration. This suspension may be formulated accordingto the known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example as a solution in 1,3-butane diol. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose any bland fixed oil may be employed includingsynthetic mono- or diglycerides. In addition, fatty acids such as oleicacid find use in the preparation of injectables.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compound of Formula I are employed. (For purposesof this application, topical application shall include mouth washes andgargles.)

The compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles anddelivery devices, or via transdermal routes, using those forms oftransdermal skin patches well known to those of ordinary skill in theart. To be administered in the form of a transdermal delivery system,the dosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen. Compounds of the presentinvention may also be delivered as a suppository employing bases such ascocoa butter, glycerinated gelatin, hydrogenated vegetable oils,mixtures of polyethylene glycols of various molecular weights and fattyacid esters of polyethylene glycol.

When a composition according to this invention is administered into ahuman subject, the daily dosage will normally be determined by theprescribing physician with the dosage generally varying according to theage, weight, and response of the individual patient, as well as theseverity of the patient's symptoms.

The dosage regimen utilizing the compounds of the instant invention canbe selected in accordance with a variety of factors including type, age,weight, sex; the route of administration; the renal and hepatic functionof the patient; and the particular compound or salt thereof employed. Anordinarily skilled physician or veterinarian can readily determine andprescribe the effective amount of the drug required to treat, forexample, to prevent, inhibit (fully or partially) or arrest the progressof the disease. For example, compounds of the instant invention can beadministered in a total daily dose of up to 10,000 mg. Compounds of theinstant invention can be administered once daily (QD), or divided intomultiple daily doses such as twice daily (BID), and three times daily(TID). Compounds of the instant invention can be administered at a totaldaily dosage of up to 10,000 mg, e.g., 2,000 mg, 3,000 mg, 4,000 mg,6,000 mg, 8,000 mg or 10,000 mg, which can be administered in one dailydose or can be divided into multiple daily doses as described above.

For example, compounds of the instant invention can be administered in atotal daily dose of up to 1,000 mg. Compounds of the instant inventioncan be administered once daily (QD), or divided into multiple dailydoses such as twice daily (BID), and three times daily (TID). Compoundsof the instant invention can be administered at a total daily dosage ofup to 1,000 mg, e.g., 200 mg, 300 mg, 400 mg, 600 mg, 800 mg or 1,000mg, which can be administered in one daily dose or can be divided intomultiple daily doses as described above.

In addition, the administration can be continuous, i.e., every day, orintermittently. The terms “intermittent” or “intermittently” as usedherein means stopping and starting at either regular or irregularintervals. For example, intermittent administration of a compound of theinstant invention may be administration one to six days per week or itmay mean administration in cycles (e.g. daily administration for two toeight consecutive weeks, then a rest period with no administration forup to one week) or it may mean administration on alternate days.

In addition, the compounds of the instant invention may be administeredaccording to any of the schedules described above, consecutively for afew weeks, followed by a rest period. For example, the compounds of theinstant invention may be administered according to any one of theschedules described above from two to eight weeks, followed by a restperiod of one week, or twice daily at a dose of 100-500 mg for three tofive days a week. In another particular embodiment, the compounds of theinstant invention may be administered three times daily for twoconsecutive weeks, followed by one week of rest.

Any one or more of the specific dosages and dosage schedules of thecompounds of the instant invention, may also be applicable to any one ormore of the therapeutic agents to be used in the combination treatment(hereinafter refered to as the “second therapeutic agent”).

Moreover, the specific dosage and dosage schedule of this secondtherapeutic agent can further vary, and the optimal dose, dosingschedule and route of administration will be determined based upon thespecific second therapeutic agent that is being used.

Of course, the route of administration of the compounds of the instantinvention is independent of the route of administration of the secondtherapeutic agent. In an embodiment, the administration for a compoundof the instant invention is oral administration. In another embodiment,the administration for a compound of the instant invention isintravenous administration. Thus, in accordance with these embodiments,a compound of the instant invention is administered orally orintravenously, and the second therapeutic agent can be administeredorally, parenterally, intraperitoneally, intravenously, intraarterially,transdermally, sublingually, intramuscularly, rectally, transbuccally,intranasally, liposomally, via inhalation, vaginally, intraoccularly,via local delivery by catheter or stent, subcutaneously,intraadiposally, intraarticularly, intrathecally, or in a slow releasedosage form.

In addition, a compound of the instant invention and second therapeuticagent may be administered by the same mode of administration, i.e. bothagents administered e.g. orally, by IV. However, it is also within thescope of the present invention to administer a compound of the instantinvention by one mode of administration, e.g. oral, and to administerthe second therapeutic agent by another mode of administration, e.g. IVor any other ones of the administration modes described hereinabove.

The first treatment procedure, administration of a compound of theinstant invention, can take place prior to the second treatmentprocedure, i.e., the second therapeutic agent, after the treatment withthe second therapeutic agent, at the same time as the treatment with thesecond therapeutic agent, or a combination thereof. For example, a totaltreatment period can be decided for a compound of the instant invention.The second therapeutic agent can be administered prior to onset oftreatment with a compound of the instant invention or followingtreatment with a compound of the instant invention.

The instant compounds are also useful in combination with othertherapeutic agents. Combinations of the presently disclosed compoundswith therapeutic agents are within the scope of the invention. A personof ordinary skill in the art would be able to discern which combinationsof agents would be useful based on the particular characteristics of thedrugs and the pathologies involved. The instant compounds are alsouseful in combination with known therapeutic agents.

The instant compounds are useful in combination with a knownanti-inflammatory agent. In one embodiment, the anti-inflammatory agentis a nonsteroidal anti-inflammatory drug (NSAID). In one embodiment, theNSAID is selected from the group consisting of salicylates,indomethacin, flurbiprofen, diclofenac, ketorolac, naproxen, piroxicam,tebufelone, ibuprofen, etodolac, nabumetone, tenidap, alcofenac,antipyrine, aminopyrine, dipyrone, aminopyrone, phenylbutazone,clofezone, oxyphenbutazone, prenazone, apazone, benzydamine, bucolome,cinchophen, clonixin, ditrazol, epirizole, fenoprofen, floctafenin,flufenamic acid, glaphenine, indoprofen, ketoprofen, loxoprofen,meclofenamic acid, mefenamic acid, niflumic acid, phenacetin,salidifamides, sulindac, suprofen, tolmetin, a pharmaceuticallyacceptable salt thereof, and a mixture thereof.

In another embodiment, the NSAID is a selective COX-2 inhibitor. Forpurposes of this specification NSAID's which are selective inhibitors ofCOX-2 are defined as those which possess a specificity for inhibitingCOX-2 over COX-1 of at least 100 fold as measured by the ratio of IC50for COX-2 over IC50 for COX-1 evaluated by cell or microsomal assays.Such compounds include, but are not limited to those disclosed in U.S.Pat. No. 5,474,995, U.S. Pat. No. 5,861,419, U.S. Pat. No. 6,001,843,U.S. Pat. No. 6,020,343, U.S. Pat. No. 5,409,944, U.S. Pat. No.5,436,265, U.S. Pat. No. 5,536,752, U.S. Pat. No. 5,550,142, U.S. Pat.No. 5,604,260, U.S. Pat. No. 5,698,584, U.S. Pat. No. 5,710,140, WO94/15932, U.S. Pat. No. 5,344,991, U.S. Pat. No. 5,134,142, U.S. Pat.No. 5,380,738, U.S. Pat. No. 5,393,790, U.S. Pat. No. 5,466,823, U.S.Pat. No. 5,633,272, and U.S. Pat. No. 5,932,598, all of which are herebyincorporated by reference.

Compounds that have been described as specific inhibitors of COX-2 andare therefore useful in the present invention include, but are notlimited to: parecoxib, CELEBREX® and BEXTRA® or a pharmaceuticallyacceptable salt thereof.

Those skilled in the art will realize that the term “cancer” to be thename for diseases in which the body's cells become abnormal and dividewithout control.

Cancers that may be treated by the compounds, compositions and methodsof the invention include, but are not limited to: Cardiac: sarcoma(angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma,rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma(squamous cell, undifferentiated small cell, undifferentiated largecell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchialadenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma,leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma,leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma,glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel(adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma,leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel(adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma)colorectal; Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor[nephroblastoma], lymphoma, leukemia), bladder and urethra (squamouscell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate(adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonalcarcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cellcarcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver:hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenicsarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma and giant celltumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma,osteitis deformans), meninges (meningioma, meningiosarcoma,gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma,germinoma [pinealoma], glioblastoma multiform, oligodendroglioma,schwannoma, retinoblastoma, congenital tumors), spinal cordneurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus(endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervicaldysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma,mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecalcell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignantteratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma),fallopian tubes (carcinoma), breast; Hematologic: blood (myeloidleukemia [acute and chronic], acute lymphoblastic leukemia, chroniclymphocytic leukemia, myeloproliferative diseases, multiple myeloma,myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma[malignant lymphoma]; Skin: malignant melanoma, basal cell carcinoma,squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi,lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands:neuroblastoma. Thus, the term “cancerous cell” as provided herein,includes a cell afflicted by any one of the above-identified conditions.

In one embodment, cancers that may be treated by the compounds,compositions and methods of the invention include, but are not limitedto: lung cancer, pancreatic cancer, colon cancer, colorectal cancer,myeloid leukemias, acute myelogenous leukemia, chronic myelogenousleukemia, chronic myelomonocytic leukemia, thyroid cancer,myelodysplastic syndrome, bladder carcinoma, epidermal carcinoma,melanoma, breast cancer, prostate cancer, head and neck cancers, ovariancancer, brain cancers, cancers of mesenchymal origin, sarcomas,tetracarcinomas, neuroblastomas, kidney carcinomas, hepatomas,non-Hodgkin's lymphoma, multiple myeloma, and anaplastic thyroidcarcinoma.

In another embodiment, cancers that may be treated by the compounds,compositions and methods of the invention include, but are not limitedto: breast, prostate, colon, colorectal, lung, brain, testicular,stomach, pancrease, skin, small intestine, large intestine, throat, headand neck, oral, bone, liver, bladder, kidney, thyroid and blood.

In another embodiment, cancers that may be treated by the compounds,compositions and methods of the invention include breast, prostate,colon, ovary, endometrium and thyroid.

In another embodiment, cancers that may be treated by the compositionsand methods of the invention include acute myeloid leukemia (AML),liposarcoma, colorectal cancer, gastric cancer and melanoma.

In a further embodiment, cancers that may be treated by the compositionsand methods of the invention include hematological malignancies, forexample acute myeloid leukemia.

In a further embodiment, cancers that may be treated by the compositionsand methods of the invention include acute lymphoblastic leukemia (ALL),lymphoma, lung, breast and glioblastoma.

The compounds of the invention are also useful in preparing a medicamentthat may be useful in treating cancer. In one embodiment, the compoundsof the invention are for the potential treatment of cancer.

The compounds of the invention may be useful to the treatment of avariety of cancers, including, but not limited to: carcinoma, including,but not limited to, of the bladder, breast, colon, rectum, endometrium,kidney, liver, lung, head and neck, esophagus, gall bladder, cervix,pancreas, prostrate, larynx, ovaries, stomach, uterus, sarcoma andthyroid cancer; hematopoietic tumors of the lymphoid lineage, includingleukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia,acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkinslymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, mantle celllymphoma, myeloma, and Burkett's lymphoma; hematopoetic tumors ofmyeloid lineage, including acute and chronic myelogenous leukemias,myelodysplastic syndrome and promyelocytic leukemia; tumors ofmesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumorsof the central and peripheral nervous system, including astrocytoma,neuroblastoma, glioma, and schwannomas; and other tumors, includingmelanoma, skin (non-melanomal) cancer, mesothelioma (cells), seminoma,teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma,thyroid follicular cancer and Kaposi's sarcoma.

The compounds of the invention may be useful for the treatment ofactivated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL), chroniclymphocytic leukemia (CLL) and Waldenström's Macroglobulinemia.

The instant compounds are useful in combination with a known anti-canceragent. Combinations of the presently disclosed compounds withanti-cancer agents are within the scope of the invention. Examples ofsuch anti-cancer agents can be found in Cancer Principles and Practiceof Oncology by V. T. Devita and S. Hellman (editors), 6th edition (Feb.15, 2001), Lippincott Williams & Wilkins Publishers. A person ofordinary skill in the art would be able to discern which combinations ofagents would be useful based on the particular characteristics of thedrugs and the cancer involved. Such agents include the following:estrogen receptor modulators, androgen receptor modulators, retinoidreceptor modulators, cytotoxic/cytostatic agents, antiproliferativeagents, prenyl-protein transferase inhibitors, HMG-CoA reductaseinhibitors and other angiogenesis inhibitors, HIV protease inhibitors,reverse transcriptase inhibitors, inhibitors of cell proliferation andsurvival signaling, bisphosphonates, aromatase inhibitors, siRNAtherapeutics, γ-secretase inhibitors, agents that interfere withreceptor tyrosine kinases (RTKs) and agents that interfere with cellcycle checkpoints.

In one embodiment, the anti-cancer agent is selected from the groupconsisting of abarelix (Plenaxis Depot®); aldesleukin (Prokine®);Aldesleukin (Proleukin®); Alemtuzumabb (Campath®); alitretinoin(Panretin®); allopurinol (Zyloprim®); altretamine (Hexalen®); amifostine(Ethyol®); anastrozole (Arimidex®); arsenic trioxide (Trisenox®);asparaginase (Elspar®); azacitidine (Vidaza®); bevacuzimab (Avastin®);bexarotene capsules (Targretin®); bexarotene gel (Targretin®); bleomycin(Blenoxane®); bortezomib (Velcade®); busulfan intravenous (Busulfex®);busulfan oral (Myleran®); calusterone (Methosarb®); capecitabine(Xeloda®); carboplatin (Paraplatin®); carmustine (BCNU®, BiCNU®);carmustine (Gliadel®); carmustine with Polifeprosan 20 Implant (GliadelWafer®); celecoxib (Celebrex®); cetuximab (Erbitux®); chlorambucil(Leukeran®); cisplatin (Platinol®); cladribine (Leustatin®, 2-CdA®);clofarabine (Clolar®); cyclophosphamide (Cytoxan®, Neosar®);cyclophosphamide (Cytoxan Injection®); cyclophosphamide (CytoxanTablet®); cytarabine (Cytosar-U®); cytarabine liposomal (DepoCyt®);dacarbazine (DTIC-Dome®); dactinomycin, actinomycin D (Cosmegen®);Darbepoetin alfa (Aranesp®); daunorubicin liposomal (DanuoXome®);daunorubicin, daunomycin (Daunorubicin®); daunorubicin, daunomycin(Cerubidine®); Denileukin diftitox (Ontak®); dexrazoxane (Zinecard®);docetaxel (Taxotere®); doxorubicin (Adriamycin PFS®); doxorubicin(Adriamycin®, Rubex®); doxorubicin (Adriamycin PFS Injection®);doxorubicin liposomal (Doxil®); dromostanolone propionate(Dromostanolone®); dromostanolone propionate (masterone Injection®);Elliott's B Solution (Elliott's B Solution®); epirubicin (Ellence®);Epoetin alfa (Epogen®); erlotinib (Tarceva®); estramustine (Emcyt®);etoposide phosphate (Etopophos®); etoposide, VP-16 (Vepesid®);exemestane (Aromasin®); Filgrastim (Neupogen®); floxuridine(intraarterial) (FUDR®); fludarabine (Fludara®); fluorouracil, 5-FU(Adrucil®); fulvestrant (Faslodex®); gefitinib (Iressa®); gemcitabine(Gemzar®); gemtuzumab ozogamicin (Mylotarg®); goserelin acetate (ZoladexImplant®); goserelin acetate (Zoladex®); histrelin acetate (HistrelinImplant®); hydroxyurea (Hydrea®); Ibritumomab Tiuxetan (Zevalin®);idarubicin (Idamycin®); ifosfamide (IFEX®); imatinib mesylate(Gleevec®); interferon alfa 2a (Roferon A®); Interferon alfa-2b (IntronA®); irinotecan (Camptosar®); lenalidomide (Revlimid®); letrozole(Femara®); leucovorin (Wellcovorin®, Leucovorin®); Leuprolide Acetate(Eligard®); levamisole (Ergamisol®); lomustine, CCNU (CeeBU®);meclorethamine, nitrogen mustard (Mustargen®); megestrol acetate(Megace®); melphalan, L-PAM (Alkeran®); mercaptopurine, 6-MP(Purinethol®); mesna (Mesnex®); mesna (Mesnex Tabs®); methotrexate(Methotrexate®); methoxsalen (Uvadex®); mitomycin C (Mutamycin®);mitotane (Lysodren®); mitoxantrone (Novantrone®); nandrolonephenpropionate (Durabolin-50®); nelarabine (Arranon®); Nofetumomab(Verluma®); Oprelvekin (Neumega®); oxaliplatin (Eloxatin®); paclitaxel(Paxene®); paclitaxel (Taxol®); paclitaxel protein-bound particles(Abraxane®); palifermin (Kepivance®); pamidronate (Aredia®); pegademase(Adagen (Pegademase Bovine)®); pegaspargase (Oncaspar®); Pegfilgrastim(Neulasta®); pemetrexed disodium (Alimta®); pentostatin (Nipent®);pipobroman (Vercyte®); plicamycin, mithramycin (Mithracin®); porfimersodium (Photofrin®); procarbazine (Matulane®); quinacrine (Atabrine®);Rasburicase (Elitek®); Rituximab (Rituxan®); sargramostim (Leukine®);Sargramostim (Prokine®); sorafenib (Nexavar®); streptozocin (Zanosar®);sunitinib maleate (Sutent®); talc (Sclerosol®); tamoxifen (Nolvadex®);temozolomide (Temodar®); teniposide, VM-26 (Vumon®); testolactone(Teslac®); thioguanine, 6-TG (Thioguanine®); thiotepa (Thioplex®);topotecan (Hycamtin®); toremifene (Fareston®); Tositumomab (Bexxar®);Tositumomab/I-131 tositumomab (Bexxar®); Trastuzumab (Herceptin®);tretinoin, ATRA (Vesanoid®); Uracil Mustard (Uracil Mustard Capsules®);valrubicin (Valstar®); vinblastine (Velban®); vincristine (Oncovin®);vinorelbine (Navelbine®); zoledronate (Zometa®) and vorinostat(Zolinza®); a pharmaceutically acceptable salt thereof, and a mixturethereof.

The term “administration” and variants thereof (e.g., “administering” acompound) in reference to a compound of the invention means introducingthe compound or a prodrug of the compound into the system of the animalin need of treatment. When a compound of the invention or prodrugthereof is provided in combination with one or more other active agents(e.g., a cytotoxic agent, etc.), “administration” and its variants areeach understood to include concurrent and sequential introduction of thecompound or prodrug thereof and other agents.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The term “therapeutically effective amount” as used herein means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician.

Further included within the scope of the invention is a method fortreating an inflammatory disease which comprises administering to amammal in need thereof a therapeutically effective amount of a compoundof the instant invention.

Further included within the scope of the invention is a method fortreating an inflammatory disease which comprises administering to amammal in need thereof a therapeutically effective amount of a compoundof the instant invention wherein the inflammatory disease is selectedfrom rheumatoid arthritis, inflammatory bowel disease and cancer.

The compounds of the instant invention are useful for the treatmentand/or reducing the severity of rheumatoid arthritis.

The compounds of the instant invention are useful for the treatmentand/or reducing the severity of inflammatory bowel disease.

The compounds of the instant invention are useful for the treatmentand/or reducing the severity of lupus.

The compounds of the instant invention are useful for the treatmentand/or reducing the severity of cancer.

The compounds of the instant invention are useful for the treatment ofrheumatoid arthritis.

The compounds of the instant invention are useful for the treatment ofinflammatory bowel disease.

The compounds of the instant invention are useful for the treatment oflupus.

The compounds of the instant invention are useful for the treatment ofcancer.

Further included within the scope of the invention is a method oftreating an inflammatory disease which comprises administering atherapeutically effective amount of a compound of the instant inventionin combination with a second therapeutic agent.

Further included within the scope of the invention is a method oftreating an inflammatory disease which comprises administering atherapeutically effective amount of a compound of the instant inventionin combination with a second therapeutic agent, wherein the secondtherapeutic agent is selected from an anti-cancer agent and ananti-inflammatory agent.

Abbreviations used in the description of the chemistry and in theExamples that follow are: Ac (Acetyl); ACN or MeCN (acetonitrile); AcOHor HOAc (acetic acid); Boc or BOC (tert-butoxycarbonyl); Bu (butyl); Bz(benzoyl); calc'd (calculated); Cbz (benyzloxycarbonyl); CDCl₃(chloroform-d); CHCl₃ (Chloroform); DAST ((diethylamino)sulfurtrifluoride); DCM (dichloromethane); DIEA or Hünig's base(N,N-diisopropylethylamine); DMAP (4-dimethylaminopyridine); DMSO(Dimethylsulfoxide); DMF (dimethylformamide); dppf(1,1′-bis(diphenylphosphino)ferrocene); Et (ethyl); EtOH (ethanol);EtOAc (ethyl acetate); g (grams); GST (glutathione S-transferase); h(hour); HATU (N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate); HCl (hydrochloric acid); HOBt(1-hydroxybenzotriazole); HPLC (high-performance liquid chromatography);IPA or iPrOH (isopropanol); iPr (isopropyl); LC (liquid chromatography);LCMS (liquid chromatography mass spectrometry); M (molar); mCPBA(m-choroperoxybenzoic acid); Me (methyl); MeOH (methanol); mg(milligrams); min (minute); μL (microliters); mL (milliliters); mmol(millimoles); MS (mass spectrometry); MTBE (methyl tert-butyl ether);NMR (nuclear magnetic resonance spectroscopy); OAc (Acetate);Pd(dppf)Cl₂(1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)); Ph(phenyl); POCl₃ (phosphorous oxychloride); Pr (propyl); rac (racemicmixture); RT or rt (room temperature (ambient, about 25° C.)); sat(saturated); SFC (supercritical fluid chromatography); tBu (tert-butyl);TEA (triethylamine (Et₃N)); TFA (trifluoroacetic acid); THF(tetrahydrofuran); TLC (thin layer chromatography); and Xantphos(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene).

General Synopsis of Reaction Schemes

The following General Reaction Schemes, Schemes 1 to 2, provide usefuldetails for preparing the instant compounds. The requisite intermediatesare in some cases commercially available or can be prepared according toliterature procedures. The illustrative General Reaction Schemes beloware not limited by the compounds listed or by any particularsubstituents employed for illustrative purposes. Substituent labelings(i.e. R groups) as shown in the Reaction Schemes do not necessarilycorrelate to that used in the claims and often, for clarity, a singlesubstituent is shown attached to the compound where multiplesubstituents are allowed under the definitions of Formula I hereinabove.

2-Chlorothieno[2,3-b]pyrazine-7-carboxylic acid (G) is prepared asdescribed in Scheme 1. 3-Chloropyrazine-2-carbonitrile is condensed withethyl 2-sulfanylacetate in the presence of sodium carbonate at anelevated temperature to afford7-aminothieno[2,3-b]pyrazine-6-carboxylate (A). Intermediate A isconverted to intermediate C via sequential Sandmeyer conditions (CuBr₂,tert-butylnitrite), saponification, and decarboxylation. Intermediate Cis then converted to intermediate D via palladium-mediated carbonylationin methanol. Intermediate D is converted to intermediate G viasequential mCPBA oxidation, chlorination and saponification.

Compounds of formula I are prepared as described in Scheme 2.Intermediate G is coupled with various aryl-amines via either amidecoupling in the presence of coupling reagents such as HATU orchlorination with oxalyl chloride followed by amide coupling of theresultant acid chloride. Intermediates H are converted to compounds Ivia S_(N)Ar coupling with an array of amines.

Intermediate 1

2-Chlorothieno[2,3-b]pyrazine-7-carboxylic acid

Step 1: Into a 2000 mL 4 necked round bottom flask purged and maintainedwith an inert atmosphere of nitrogen were placed a solution of3-chloropyrazine-2-carbonitrile (100 g, 716 mmol) in ethanol (660 mL),ethyl 2-sulfanylacetate (112 g, 932 mmol) and sodium carbonate (99 g,930 mmol). The resulting solution was stirred for 4.5 h at 100° C. in anoil bath. The reaction mixture was cooled to room temperature and pouredinto 7.5 L of water. The solid was collected by filtration. The solidwas dissolved in 1500 mL of ethyl ether and filtered. The filtrate wasconcentrated under reduced pressure. This resulted in ethyl7-aminothieno[2,3-b]pyrazine-6-carboxylate as a solid.

Step 2: Into a 2000 mL 4 necked round bottom flask purged and maintainedwith an inert atmosphere of nitrogen were placed a solution oft-butylnitrite (42.4 g, 411 mmol) in acetonitrile (700 mL) and CuBr₂(79.2 g, 355 mmol). This was followed by the addition of ethyl7-aminothieno[2,3-b]pyrazine-6-carboxylate (72 g, 323 mmol) in severalbatches at 0° C. over 2 h. The resulting solution was stirred for 1 h atroom temperature. The reaction was treated with 400 mL of aqueousammonia. The resulting solution was extracted with 2×1000 mL of ethylacetate and the combined organic layers were dried over anhydrous sodiumsulfate. The mixture was filtered, concentrated under reduced pressureand purified by flash chromatography to afford ethyl7-bromothieno[2,3-b]pyrazine-6-carboxylate as a solid.

Step 3: Into a 1000 mL 4 necked round bottom flask purged and maintainedwith an inert atmosphere of nitrogen was placed a solution of ethyl7-bromothieno[2,3-b]pyrazine-6-carboxylate (52 g, 180 mmol) in ethanol(150 mL). This was followed by the addition of sodium hydroxide (172 mL,2 N) in portions at room temperature. The resulting solution was stirredfor 5 min at room temperature. The pH value of the solution was adjustedto 3-4 with hydrogen chloride (2 N). The solids were collected byfiltration and dried in an oven under reduced pressure. This resulted in7-bromothieno[2,3-b]pyrazine-6-carboxylic acid as a solid.

Step 4: Into a 2000 mL 4 necked round bottom flask purged and maintainedwith an inert atmosphere of nitrogen were placed a solution of7-bromothieno[2,3-b]pyrazine-6-carboxylic acid (100 g, 386 mmol) inN,N-dimethylformamide (1000 mL), Ag₂CO₃ (5.3 g, 19 mmol) and AcOH (1.1g, 18 mmol). The resulting solution was stirred for 4 h at 120° C. in anoil bath. The reaction mixture was cooled to room temperature andextracted with 2×1000 mL of ether. The combined organics were dried overanhydrous sodium sulfate, filtered, concentrated, and purified by flashchromatography eluting with ethyl acetate/petroleum ether (1:30) toafford 7-bromothieno[2,3-b]pyrazine as a solid.

Step 5: Into a 1000 mL pressure tank reactor (15 atm) were placed asolution of 7-bromothieno[2,3-b]pyrazine (40 g, 190 mmol) in methanol(400 mL), Pd(dppf)Cl₂.CH₂Cl₂ (7.6 g) and triethylamine (94 g, 930 mmol).Into the mixture was introduced CO and the resulting solution wasstirred overnight at 100° C. The reaction mixture was cooled to roomtemperature, concentrated under reduced pressure, and purified by flashchromatography eluting with ethyl acetate/petroleum ether (1:3) toafford methyl thieno[2,3-b]pyrazine-7-carboxylate as a solid.

Step 6: Into a 1000 mL 4 necked round bottom flask purged and maintainedwith an inert atmosphere of nitrogen were placed a solution of methylthieno[2,3-b]pyrazine-7-carboxylate (20 g, 100 mmol) in dichloromethane(200 mL) and mCPBA (3.6 g). The resulting solution was stirred overnightat room temperature, concentrated under reduced pressure and purified byflash chromatography eluting with ethyl acetate/petroleum ether (1:3) toafford methyl thieno[2,3-b]pyrazine-7-carboxylate 1-oxide as a solid.

Step 7: Into a 1000 mL 4 necked round bottom flask purged and maintainedwith an inert atmosphere of nitrogen were placed a solution of methylthieno[2,3-b]pyrazine-7-carboxylate 1-oxide (21.5 g, 102 mmol) in CH₃CN(220 mL), POCl₃ (47 g, 310 mmol) and N-dimethylaniline (18.6 g, 153mmol). The resulting solution was stirred for 2 h at 40° C. in an oilbath, cooled to room temperature and concentrated under reducedpressure. The residue was treated with 400 mL of water/ice and the solidwas collected by filtration and dried in an oven under reduced pressure.This resulted in methyl 2-chlorothieno[2,3-b]pyrazine-7-carboxylate as asolid.

Step 8: Into a 2000 mL 4 necked round bottom flask purged and maintainedwith an inert atmosphere of nitrogen were placed a solution of methyl2-chlorothieno[2,3-b]pyrazine-7-carboxylate (20 g, 87 mmol) intetrahydrofuran/H₂O (500/200 mL) and LiOH (3.8 g, 160 mmol). Theresulting solution was stirred for 2 h at room temperature and washedwith 2×500 mL of ether. The pH value of the aqueous layer was adjustedto 2-3 with hydrogen chloride (1.5 N). The solids were collected byfiltration and dried in an oven under reduced pressure to afford2-chlorothieno[2,3-b]pyrazine-7-carboxylic acid as a solid. ¹H NMR(CDCl₃, 300 MHz): δ 13.44 (s, 1H), 9.14 (s, 1H), 3.87 (s, 1H). MS [M+H]+215.

Intermediate 2

3-(Difluoromethyl)-1-methyl-1H-pyrazol-4-amine

Step 1: Into a 100 mL round bottom flask containing a solution of methyl1-methyl-4-nitro-1H-pyrazole-3-carboxylate (1.5 g, 8 mmol) indichloromethane (30 mL) was added diisobutylaluminum hydride (12 mL, 1 Min toluene, 12 mmol) at 0° C. and the reaction mixture was stirred atroom temperature for 6 h. The reaction mixture was treated withhydrochloric acid (1.5 N, 1 mL) and extracted with ethyl acetate. Theorganic fraction was dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashchromatography eluting with methanol in dichloromethane (5-10%) to yield(1-methyl-4-nitro-1H-pyrazol-3-yl)methanol as a solid. ¹H NMR (DMSO-d₆,300 MHz): δ 8.77 (s, 1H), 5.19 (t, J=5.9 Hz, 1H), 4.63 (d, J=5.9 Hz,2H), 3.85 (s, 3H).

Step 2: Into a 50 mL round bottom flask containing a solution of2-iodoxybenzoic acid (2.8 g, 10 mmol) in dimethyl sulfoxide (3 mL) wasadded a solution of (1-methyl-4-nitro-1H-pyrazol-3-yl)methanol (800 mg,5 mmol) in dimethyl sulfoxide (3 mL) and the reaction mixture wasstirred at room temperature for 3 h. The reaction mixture was dilutedwith diethyl ether and washed with water and brine. The organic fractionwas dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by flash chromatographyeluting with methanol in dichloromethane (7-9%) to yield1-methyl-4-nitro-1H-pyrazole-3-carbaldehyde as a solid. ¹H NMR (CDCl₃,400 MHz): δ 10.43 (s, 1H), 8.25 (s, 1H), 4.09 (s, 3H).

Step 3: Into a 25 mL round bottom flask containing a solution of1-methyl-4-nitro-1H-pyrazole-3-carbaldehyde (300 mg, 1.9 mmol) indichloromethane (5 mL) was added diethylaminosulfur trifluoride (0.76mL, 5.8 mmol) at −20° C. and the reaction was stirred at roomtemperature for 16 h. The reaction mixture was concentrated underreduced pressure and the residue was purified by flash chromatographyeluting with methanol in dichloromethane (3-5%) to yield3-(difluoromethyl)-1-methyl-4-nitro-1H-pyrazole. ¹H NMR (CDCl₃, 400MHz): δ 8.19 (s, 1H), 7.13 (t, J=53.2 Hz, 1H), 4.03 (s, 3H).

Step 4: Into a 25 mL round bottom flask containing a solution of3-(difluoromethyl)-1-methyl-4-nitro-1H-pyrazole (300 mg, 1.93 mmol) inmethanol (3 mL) was added palladium on carbon (15 mg, 5% w/w) and thereaction was stirred at room temperature for 8 h under hydrogen bladderpressure. The reaction mixture was filtered through celite and washedwith methanol and the filtrate was concentrated under reduced pressure.The residue was purified by flash chromatography eluting with methanolin dichloromethane (4-7%) to yield3-(difluoromethyl)-1-methyl-1H-pyrazol-4-amine. ¹H NMR (CDCl₃, 400 MHz):δ 7.09 (s, 1H), 6.86 (t, J=54.1 Hz, 1H), 3.70 (s, 3H). MS calc'd [M+H]⁺148.1, found 148.2.

Intermediate 3

4-Amino-1-methyl-1H-pyrazole-3-carbonitrile

Step 1: Into a 250 mL round bottom flask containing a suspension of4-nitro-1H-pyrazole-3-carboxylic acid (20.0 g, 127 mmol) in methanol(100 mL) was added concentrated sulfuric acid (4 mL) dropwise over 5 minat 0° C. and the resulting slurry was refluxed at 80° C. for 16 h. Thesolvent was removed under reduced pressure and the residual mass wasdissolved in ethyl acetate (300 mL) and washed with saturated aqueoussodium bicarbonate solution (2×100 mL) and brine (100 mL) and dried overanhydrous sodium sulfate. The solution was filtered and concentratedunder reduced pressure to give methyl 4-nitro-1H-pyrazole-3-carboxylateas a solid. The crude product was taken to the next step without furtherpurification. MS calc'd [M−H]⁺170.0, found 170.0.

Step 2: Into a 1 L round bottom flask containing a suspension of sodiumhydride (60% in paraffin oil, 4.7 g, 116 mmol) in tetrahydrofuran (400mL) at 0° C. was added methyl 4-nitro-1H-pyrazole-3-carboxylate (16.5 g,96 mmol) in tetrahydrofuran (50 mL) dropwise and the reaction mixturewas stirred for 1 h. To the reaction mixture was added methyl iodide (9mL, 145 mmol) and the mixture was stirred at room temperature for 3 h.The reaction mixture was cooled to 0° C. and treated with saturatedaqueous ammonium chloride solution and extracted with ethyl acetate(4×200 mL). The combined organic fractions were washed with brine (100mL), dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by flash chromatographyeluting with ethyl acetate in petroleum ether (15-25%) to afford methyl1-methyl-4-nitro-1H-pyrazole-3-carboxylate as a solid. ¹H NMR (CDCl₃,400 MHz): δ 8.17 (s, 1H), 4.03 (s, 3H), 4.01 (s, 3H).

Step 3: Into a 250 mL sealed tube were added methyl1-methyl-4-nitro-1H-pyrazole-3-carboxylate (2.5 g, 13.5 mmol) andmethanol (60 mL) and the reaction mixture was cooled to −60° C. andammonia gas was purged for 15 min and then heated at 80° C. for 4 h. Thereaction mixture was cooled to −15° C. and the excess ammonia gas wascarefully removed by bubbling nitrogen and concentrated under reducedpressure to afford 1-methyl-4-nitro-1H-pyrazole-3-carboxamide as asolid. 1H NMR (CD₃OD, 300 MHz): δ 8.56 (s, 1H), 3.94 (s, 3H). MS calc'd[M+H]⁺ 171.0, found 171.2.

Step 4: Into a 250 mL sealed tube containing a solution of1-methyl-4-nitro-1H-pyrazole-3-carboxamide (2.0 g, 12 mmol) indichloromethane (100 mL) was added N,N-diisopropylethylamine (13 mL, 71mmol) at 0° C. To this reaction mixture was added phosphorousoxychloride (3.3 mL, 35 mmol) dropwise and the mixture was stirred atroom temperature for 1 h. The reaction was treated with saturated sodiumbicarbonate solution and extracted with dichloromethane. The combinedorganics were washed with water and brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash chromatography eluting with ethyl acetate inpetroleum ether (25-30%) to afford1-methyl-4-nitro-1H-pyrazole-3-carbonitrile as a solid. ¹H NMR (CDCl₃,400 MHz): δ 8.24 (s, 1H), 4.09 (s, 3H).

Step 5: Into a 250 mL round bottom flask containing a solution of1-methyl-4-nitro-1H-pyrazole-3-carbonitrile (3.5 g, 23 mmol) in methanol(100 mL) at room temperature was added palladium on carbon (0.5 g, 15%w/w) and the reaction mixture was stirred at room temperature underhydrogen bladder atmosphere for 2 h. The reaction mixture was filteredthrough celite and washed with methanol and dichloromethane. Thefiltrate was concentrated under reduced pressure to afford4-amino-1-methyl-1H-pyrazole-3-carbonitrile as a solid. ¹H NMR (CD₃OD,400 MHz): δ 7.22 (s, 1H), 3.84 (s, 3H). MS calc'd [M+H]⁺ 123.1, found123.4.

Intermediate 4

3-Bromo-1-methyl-1H-pyrazol-4-amine

Step 1: Into a 250 mL round bottom flask containing a solution of3-amino-1-methyl-1H-pyrazole (5.0 g, 52 mmol) in dichloromethane (100mL) at 0° C. was added triethylamine (18 mL, 129 mmol). After 10 min,trifluoroacetic anhydride (9.5 mL, 67 mmol) was added and the reactionmixture was stirred at room temperature for 2 h. The reaction mixturewas diluted with dichloromethane (50 mL), washed with water and brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to afford2,2,2-trifluoro-N-(1-methyl-1H-pyrazol-3-yl)acetamide as a solid. ¹H NMR(CDCl₃, 400 MHz): δ 9.26 (brs, 1H), 7.33 (d, J=2.2 Hz, 1H), 6.73 (d,J=2.2 Hz, 1H), 3.84 (s, 3H). MS calc'd [M+H]⁺ 194.1, found 194.4.

Step 2: Into a 100 mL round bottom flask containing a solution of2,2,2-trifluoro-N-(1-methyl-1H-pyrazol-3-yl)acetamide (8.5 g, 44 mmol)in concentrated sulfuric acid (14 mL) was added fuming nitric acid (14mL) at 0° C. dropwise and the reaction was stirred at room temperaturefor 2 h. The reaction mixture was treated with ice cold water andextracted with ethyl acetate. The combined organic fractions were washedwith saturated sodium bicarbonate solution, water and brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to afford2,2,2-trifluoro-N-(1-methyl-4-nitro-1H-pyrazol-3-yl)acetamide (8.5 g)which was taken to the next step without further purification. ¹H NMR(CDCl₃, 300 MHz): δ 9.86 (s, 1H), 8.15 (s, 1H), 3.98 (s, 3H). MS calc'd[M−H]⁺237.0, found 237.0.

Step 3: Into a 500 mL round bottom flask containing a solution of2,2,2-trifluoro-N-(1-methyl-4-nitro-1H-pyrazol-3-yl)acetamide (8.5 g, 36mmol) in methanol (200 mL) and water (50 mL) was added potassiumcarbonate (12.5 g, 89 mmol) and the reaction was stirred at roomtemperature for 24 h. The mixture was concentrated under reducedpressure and the residue was dissolved in ethyl acetate (150 mL), washedwith water and brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography eluting with ethyl acetate to afford1-methyl-4-nitro-1H-pyrazol-3-amine as a solid. ¹H NMR (DMSO-d₆, 300MHz): δ 8.44 (s, 1H), 6.22 (s, 2H), 3.65 (s, 3H). MS calc'd [M+H]⁺143.1, found 143.2.

Step 4: Into a 250 mL round bottom flask containing a solution ofcopper(II) bromide (3.0 g, 14 mmol) and tert-butyl nitrite (1.7 mL, 14mmol) in acetonitrile (150 mL) was added1-methyl-4-nitro-1H-pyrazol-3-amine (2 g, 14 mmol) in acetonitrile (20mL) at 0° C. and the reaction was stirred at room temperature for 2 h.The reaction mixture was concentrated under reduced pressure. Theresidue was dissolved in ethyl acetate (120 mL), washed with water andbrine, dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by columnchromatography eluting with ethyl acetate in petroleum ether (20-30%) toafford 3-bromo-1-methyl-4-nitro-1H-pyrazole as a solid. ¹H NMR (CDCl₃,300 MHz): δ 8.25 (s, 1H), 3.89 (s, 3H).

Step 5: Into a 100 mL round bottom flask containing a solution of3-bromo-1-methyl-4-nitro-1H-pyrazole (1.0 g) in ethyl acetate (50 mL) atroom temperature was added Raney Nickel (700 mg) and the reactionmixture was stirred at room temperature for 16 h under hydrogenatmosphere. The reaction mixture was filtered through celite and washedwith ethyl acetate. The filtrate was concentrated under reduced pressureand purified by flash chromatography eluting with ethyl acetate inpetroleum ether (40-50%) to afford 3-bromo-1-methyl-1H-pyrazol-4-amineas a liquid. ¹H NMR (CD₃OD, 400 MHz): δ 7.18 (s, 1H), 3.77 (s, 3H). MScalc'd [M+H]⁺ 176.0, found 176.2.

Intermediate 5

3-Chloro-1-methyl-1H-pyrazol-4-amine

Step 1: Into a 250 mL round bottom flask containing a solution of1-methyl-4-nitro-1H-pyrazol-3-amine (4.0 g, 28 mmol) in acetonitrile(100 mL) was added concentrated hydrochloric acid (8 mL) dropwise at 0°C. To this reaction mixture was added sodium nitrite (8.0 g, 116 mmol)in portions and the reaction mixture was gradually brought to roomtemperature and stirred for 16 h. The reaction mixture was cooled to 0°C., treated with water (30 mL) and extracted with ethyl acetate (2×50mL). The combined organics were washed with saturated sodium bicarbonatesolution, water and brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified bycolumn chromatography eluting with ethyl acetate in petroleum ether(20-30%) to furnish 3-chloro-1-methyl-4-nitro-1H-pyrazole as a solid. ¹HNMR (CDCl₃, 300 MHz): δ 8.25 (s, 1H), 3.98 (s, 3H).

Step 2: Into a 100 mL round bottom flask containing a solution of3-chloro-1-methyl-4-nitro-1H-pyrazole (2.0 g) in ethyl acetate (50 mL)was added Raney Ni (1.0 g) and the reaction mixture was stirred underhydrogen atmosphere for 24 h. The reaction mixture was filtered throughcelite and washed with ethyl acetate. The filtrate was concentratedunder reduced pressure and purified by flash chromatography eluting withethyl acetate in petroleum ether (40-50%) to afford3-chloro-1-methyl-1H-pyrazol-4-amine as an oil. ¹H NMR (CD₃OD, 400 MHz):δ 7.17 (s, 1H), 3.73 (s, 3H).

Intermediate 6

2-Bromo-3-aminothiophene hydrobromide

Step 1: Into a 100 mL round bottom flask containing a solution ofthiophene-3-carboxylic acid (4.0 g, 31 mmol) in toluene (40 mL) wereadded diphenylphosphoryl azide (9.5 g, 34 mmol) andN,N-diisopropylethylamine (6.7 mL, 38 mmol) at 0° C. and the reactionwas stirred at room temperature for 1 h. The reaction mixture was cooledto 0° C., treated with tert-butanol (12 mL, 124 mmol) and heated to 120°C. for 5 h. The reaction mixture was concentrated under reduced pressureand purified by flash chromatography eluting with ethyl acetate inpetroleum ether (2-5%) to afford tert-butyl thiophen-3-ylcarbamate as asolid. ¹H NMR (CDCl₃, 400 MHz): δ 7.23-7.21 (m, 2H), 6.93 (d, J=5.6 Hz,1H), 6.71 (brs, 1H), 1.54 (s, 9H).

Step 2: Into a 100 mL round bottom flask containing a solution oftert-butyl thiophen-3-ylcarbamate (4.2 g, 21 mmol) in carbontetrachloride (40 mL) was added N-bromosuccinimide (7.5 g, 42 mmol) andthe reaction mixture was heated at 80° C. for 2 h. The reaction mixturewas diluted with ethyl acetate (100 mL), washed with water and brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by flash chromatographyeluting with ethyl acetate in petroleum ether (2-5%) to affordtert-butyl (2-bromothiophen-3-yl)carbamate as a solid. ¹H NMR (CDCl₃,400 MHz): δ 7.59 (d, J=3.3 Hz, 1H), 7.26 (d, J=3.4 Hz, 1H), 6.58 (brs,1H), 1.54 (s, 9H). MS calc'd [M+H]⁺ 278.0, found 278.2.

Step 3: Into a 10 mL round bottom flask containing a solution oftert-butyl (2-bromothiophen-3-yl)carbamate (500 mg) in dichloromethane(5 mL) was added HBr in acetic acid (0.5 mL) dropwise at 0° C. andreaction mixture was stirred at room temperature for 2 h. The reactionmixture was concentrated under reduced pressure and triturated usingdiethyl ether to afford 2-bromothiophen-3-amine hydrobromide as a solid.¹H NMR (DMSO-d₆, 400 MHz): (7.66 (d, J=5.8 Hz, 1H), 6.96 (d, J=5.8 Hz,1H).

The following intermediate was prepared in an analogous manner of thatdescribed in Intermediate 6.

Exact Mass Intermediate # Structure IUPAC Name [M + 11]⁺ 7

2-chlorothiophen-3- amine hydrochloride Calc’d 134.0, found 134.4

Intermediate 8

2-(Trifluoromethyl)thiophen-3-amine hydrobromide

Step 1: Into a 50 mL round bottom flask containing a solution oftert-butyl thiophen-3-ylcarbamate (1.0 g, 5 mmol) in tert-butanol (30mL) were added 1-(trifluoromethyl)-1λ³,2-benziodoxol-3(1H)-one (3.3 g,10 mmol) and copper(I) chloride (100 mg, 1 mmol) and the reaction washeated at 115° C. for 8 h. The reaction mixture was diluted with ethylacetate (20 mL) and washed with saturated sodium bicarbonate solution,water and brine. The solution was dried over anhydrous sodium sulfate,filtered, concentrated under reduced pressure and purified by flashcolumn chromatography eluting with ethyl acetate in petroleum ether(15-20%) to furnish tert-butyl(2-(trifluoromethyl)thiophen-3-yl)carbamate as a solid. ¹H NMR (CDCl₃,300 MHz): δ 7.77 (d, J=4.4 Hz, 1H), 7.38 (d, J=5.5 Hz, 1H), 6.91 (brs,1H), 1.53 (s, 9H).

Step 2: Into a 25 mL round bottom flask tert-butyl(2-(trifluoromethyl)thiophen-3-yl)carbamate (800 mg) in dichloromethane(10 mL) was added HBr in acetic acid (1 mL) at 0° C. and the mixture wasstirred at room temperature for 2 h. The reaction mixture wasconcentrated under reduced pressure and triturated using diethyl etherto afford 2-(trifluoromethyl)thiophen-3-amine hydrobromide as a solid.¹H NMR (DMSO-d₆, 300 MHz): δ 7.51 (d, J=5.2 Hz, 1H), 6.59 (d, J=4.0 Hz,1H).

Intermediate 9

4-Bromo-3-aminothiophene

Step 1: Into a 100 mL round bottom flask containing a solution of3,4-dibromothiophene (5.0 g, 21 mmol) in toluene (50 mL) were addedbenzophenone imine (4.1 g, 23 mmol), palladium acetate (140 mg, 0.6mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (510 mg, 0.83 mmol)and cesium carbonate (13.4 g, 41 mmol) and the reaction mixture wasdegassed for 15 min using nitrogen gas and heated at 110° C. for 16 h.The reaction mixture was filtered through celite and washed with ethylacetate. The filtrate was concentrated under reduced pressure andpurified by flash column chromatography eluting with ethyl acetate inpetroleum ether (2-5%) to affordN-(4-bromothiophen-3-yl)-1,1-diphenylmethanimine as a solid. ¹H NMR(CDCl₃, 400 MHz): δ 7.85-7.82 (m, 3H), 7.64-7.60 (m, 2H), 7.53-7.49 (m,3H), 7.45-7.42 (m, 1H), 7.39-7.36 (m, 2H), 7.23-7.18 (m, 1H). MS calc'd[M+H]+ 342.0, found 342.0.

Step 2: Into a 50 mL round bottom flask containing a solution ofN-(4-bromothiophen-3-yl)-1,1-diphenylmethanimine (4.0 g, 12 mmol) indichloromethane (20 mL) was added hydrochloric acid (4 M solution in1,4-dioxane, 10 mL) at 0° C. and the reaction was stirred at roomtemperature for 4 h. The reaction mixture was concentrated under reducedpressure, triturated using diethyl ether and dried under high vacuum toafford 4-bromothiophen-3-amine hydrochloride as a solid. ¹H NMR (CDCl₃,400 MHz): (7.15 (d, J=3.6 Hz, 1H), 6.25 (d, J=3.6 Hz, 1H). MS calc'd[M+H]⁺ 177.9, found 178.2.

Intermediate 10

4-Chlorothiophen-3-amine

Step 1: Into a 250 mL round bottom flask containing a solution of methyl4-aminothiophene-3-carboxylate (2.5 g, 16 mmol) in concentratedhydrochloric acid (21 mL) was added sodium nitrite (1.2 g, 18 mmol) inwater (5 mL) dropwise at 0° C. and the reaction mixture was stirred atfor 1 h. The mixture was treated with copper(I) chloride (2.5 g, 19mmol) in chloroform (25 mL) and heated at 50° C. for 16 h. The reactionmixture was cooled to room temperature, treated with saturated sodiumcarbonate solution and extracted with dichloromethane (3×50 mL). Thecombined organic layers were washed with water and brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash chromatography eluting withethyl acetate in petroleum ether (0-4%) to furnish methyl4-chlorothiophene-3-carboxylate as a liquid. ¹H NMR (CDCl₃, 400 MHz): δ8.13 (d, J=3.7 Hz, 1H), 7.20 (d, J=3.7 Hz, 1H), 3.90 (s, 3H).

Step 2: Into a 25 mL round bottom flask containing a solution of methyl4-chlorothiophene-3-carboxylate (600 mg, 3.4 mmol) in tetrahydrofuran (6mL) and water (1 mL) was added lithium hydroxide monohydrate (240 mg, 10mmol) and the reaction was stirred at room temperature for 16 h. Themixture was concentrated under reduced pressure and acidified to pH 2using diluted hydrochloric acid (1.5 N). The reaction mixture wasextracted with ethyl acetate. The combined organic fractions were washedwith water and brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to afford4-chlorothiophene-3-carboxylic acid as a liquid. ¹H NMR (CDCl₃, 300MHz): δ 8.29 (d, J=3.7 Hz, 1H), 6.57 (d, J=3.6 Hz, 1H). MS calc'd[M−H]⁺161.0, found 161.0.

Step 3: Into a 100 mL round bottom flask containing a solution of4-chlorothiophene-3-carboxylic acid (500 mg, 3 mmol) in toluene (20 mL)were added diphenylphosphoryl azide (2.5 g, 3.4 mmol) andN,N-diisopropylethylamine (0.7 mL, 3.7 mmol) and the reaction wasstirred at room temperature for 1 h. To this mixture was addedtert-butanol (1.2 mL, 12 mmol) and the mixture was heated at 100° C. for3 h. The reaction mixture was concentrated under reduced pressure,diluted with ethyl acetate (120 mL), washed with water and brine, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by column chromatography eluting withethyl acetate in petroleum ether (2-4%) to furnish tert-butyl(4-chlorothiophen-3-yl)carbamate as a solid. ¹H NMR (CDCl₃, 400 MHz):(7.53 (d, J=4.8 Hz, 1H), 7.11 (d, J=3.6 Hz, 1H), 6.82 (brs, 1H), 1.43(s, 9H). MS calc'd [M-Boc+H]⁺134.0, found 134.4.

Step 4: Into a 10 mL round bottom flask containing a solution oftert-butyl (4-chlorothiophen-3-yl)carbamate (400 mg, 1.7 mmol) indichloromethane (4 mL) was added hydrochloric acid solution (4M solutionin 1,4-dioxane, 0.3 mL) and the reaction mixture was stirred at roomtemperature for 2 h. The reaction mixture was concentrated under reducedpressure, triturated with diethyl ether and dried under high vacuum toafford 4-chlorothiophen-3-amine hydrochloride as a solid. ¹H NMR (CD₃OD,400 MHz): δ 7.64 (s, 2H). MS calc'd [M+H]⁺134.0, found 134.4.

Intermediate 11

4-(Difluoromethyl)thiophen-3-amine

Step 1: Into a 100 mL round bottom flask containing a solution of3,4-dibromothiophene (4.0 g, 17 mmol) in diethyl ether (50 mL) was addedn-butyl lithium in hexane (1 M solution in hexanes, 17 mL, 17 mmol) at−78° C. over 15 min. To this mixture was added N,N-dimethylformamide andthe reaction was stirred for 3 h. The reaction mixture was treated withsaturated ammonium chloride solution and extracted with diethyl ether(2×50 mL). The combined organics were washed with water and brine, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure to furnish 4-bromothiophene-3-carbaldehyde as a liquid whichwas directly taken to the next step without further purification. ¹H NMR(CDCl₃, 400 MHz): δ 9.99 (s, 1H), 8.17 (s, 1H), 7.76 (s, 1H).

Step 2: Into a 50 mL round bottom flask containing a solution of4-bromothiophene-3-carbaldehyde (3.5 g, 18 mmol) in dichloromethane (40mL) was added diethylaminosulfur trifluoride (7.3 mL, 55 mmol) at 0° C.and the reaction was stirred room temperature for 16 h.

The reaction mixture was diluted with dichloromethane (20 mL) and washedwith saturated sodium bicarbonate solution, water and brine. Thesolution was dried over anhydrous sodium sulfate, filtered, concentratedunder reduced pressure and purified by flash column chromatographyeluting with ethyl acetate in petroleum ether (2-5%) to furnish3-bromo-4-(difluoromethyl)thiophene as a liquid. ¹H NMR (CDCl₃, 300MHz): δ 7.68 (s, 1H), 7.35 (s, 1H), 6.67 (t, J=55.1 Hz, 1H).

Step 3: A solution of 3-bromo-4-(difluoromethyl)thiophene (800 mg, 4mmol) in N,N-dimethylformamide (10 mL) at 0° C. was purged with ammoniagas for 1 h. To this mixture were added potassium phosphate tribasic(2.4 g, 11 mmol) and copper(II) acetylacetonate (300 mg, 1.9 mmol) andthe reaction mixture was heated at 90° C. for 16 h. The reaction mixturewas diluted with ethyl acetate (20 mL), washed with water and brine,dried over anhydrous sodium sulfate, filtered, concentrated underreduced pressure and purified by flash column chromatography elutingwith ethyl acetate in petroleum ether (15-20%) to furnish4-(difluoromethyl)thiophen-3-amine as a liquid. ¹H NMR (CDCl₃, 300 MHz):δ 7.36 (d, J=2.9 Hz, 1H), 6.63 (t, J=55.7 Hz, 1H), 6.24 (d, J=3.3 Hz,1H). MS calc'd [M+H]⁺ 150.0, found 150.4.

Intermediate 12

2-(Difluoromethyl)aniline hydrobromide

Step 1: Into a 250 mL round bottom flask containing a solution of methyl2-formylbenzoate (5.0 g, 30 mmol) in dichloromethane (80 mL) were addeddiethylaminosulfur trifluoride (7 mL, 52 mmol) and methanol (1.5 mL) at−5° C. and the reaction was stirred at room temperature for 16 h. Thereaction mixture was diluted with dichloromethane (20 mL) and washedwith saturated sodium bicarbonate solution, water and brine. Thesolution was dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to afford methyl2-(difluoromethyl)benzoate as an oil which was taken to the next stepwithout further purification.

Step 2: Into a 100 mL round bottom flask containing a solution of methyl2-(difluoromethyl)benzoate (4.3 g, 23 mmol) in tetrahydrofuran (30 mL)and water (15 mL) was added lithium hydroxide monohydrate (2.9 g, 69mmol) at 0° C. and the reaction mixture was stirred at room temperaturefor 16 h. The reaction mixture was concentrated under reduced pressureand acidified to pH 2 using diluted hydrochloric acid (1.5 N). Thereaction mixture was extracted with ethyl acetate. The combined organicswere washed with water and brine, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to afford2-(difluoromethyl)benzoic acid (4.0 g). The crude product was taken tothe next step without further purification. MS calc'd [M−H]⁺171.0, found171.0.

Step 3: Into a 100 mL round bottom flask containing a solution of2-(difluoromethyl)benzoic acid (4.0 g, 23 mmol) in toluene (50 mL) wereadded diphenylphosphoryl azide (5.5 mL, 26 mmol),N,N-diisopropylethylamine (5 mL, 28 mmol) and tert-butanol (7 mL) andthe mixture was stirred at room temperature for 30 min and at 110° C.for 16 h. The reaction mixture was concentrated under reduced pressure.The residue was dissolved in ethyl acetate (120 mL), washed with waterand brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography eluting with ethyl acetate in petroleum ether (5-10%) tofurnish tert-butyl (2-(difluoromethyl)phenyl)carbamate as a liquid. ¹HNMR (CDCl₃, 300 MHz): δ 8.01 (d, J=8.2 Hz, 1H), 7.49-7.38 (m, 2H), 7.14(t, J=7.5 Hz, 1H), 6.86 (brs, 1H), 6.68 (t, J=55.1 Hz, 1H), 1.53 (s,9H).

Step 4: Into a 10 mL round bottom flask containing a solution oftert-butyl (2-(difluoromethyl)phenyl)carbamate (650 mg) indichloromethane (5 mL) was added HBr in acetic acid (0.5 mL) at 0° C.and the reaction was stirred at room temperature for 2 h. The reactionmixture was concentrated under reduced pressure, triturated with diethylether and dried under high vacuum to afford 2-(difluoromethyl)anilinehydrobromide as a solid. ¹H NMR (DMSO-d₆, 400 MHz): δ 7.37-7.35 (m, 1H),7.32-7.28 (m, 1H), 7.07 (t, J=55.2 Hz, 1H), 6.95-6.93 (m, 1H), 6.88-6.84(m, 1H). MS calc'd [M+H]⁺ 144.1, found 144.4.

Intermediate 13

tert-Butyl 5,8-diazaspiro[2.6]nonane-5-carboxylate

Step 1: Into a 5 L 4 necked round bottomed flask was placed a solutionof diethyl malonate (300 g, 1.87 mol) and 1,2-dibromoethane (634.5 g,3.38 mol) in DMSO (1.5 L). The mixture was treated with K₂CO₃ (1020 g,7.39 mol) and Bu₄NHSO₄ (6.4 g, 19 mmol). The resulting solution wasallowed to stir for 48 h at room temperature. The reaction mixture wastreated with 2 L of H₂O and extracted with 1.5 L of EtOAc (3×). Theorganic layers were combined, dried over Na₂SO₄ and concentrated underreduced pressure. The residue was distilled under 5-10 mmHg vacuum at64-65° C. This resulted in 400 g (90%) of diethylcyclopropane-1,1-dicarboxylate as an oil.

Step 2: Into a 100 mL 3 necked round bottomed flask was placed THF (50mL), then added LiAlH₄ (2 g, 53 mmol) in several batches. This wasfollowed by the addition of a solution of diethylcyclopropane-1,1-dicarboxylate (5 g, 27 mmol) in THF (10 mL) dropwisewith stirring, while cooling to 0° C. The resulting solution was allowedto stir for 1 h at 0-5° C. in an ice bath. The reaction mixture was thentreated with 2 mL of H₂O, 6 mL of 15% NaOH solution and 2 mL of H₂O. Themixture was filtered and the filtrate was concentrated under reducedpressure. The residue was extracted with 50 mL of EtOAc. The organiclayer was dried over Na₂SO₄ and concentrated under reduced pressure toafford cyclopropane-1,1-diyldimethanol as a liquid.

Step 3: Into a 2 L 3 necked round bottomed flask were placed a solutionof cyclopropane-1,1-diyldimethanol (42 g, 410 mmol) in DCM (200 mL) andDMAP (126 g, 1.03 mol). The mixture was treated with a solution of TsCl(173 g, 907 mmol) in DCM (500 mL) dropwise, while cooling to 0° C., over30 min. The resulting solution was allowed to stir for 2.5 h at roomtemperature. The reaction mixture was washed with H₂O, HCl (1N) andbrine, dried over Na₂SO₄ and concentrated under reduced pressure. Thisresulted in cyclopropane-1,1-diyldimethanediylbis(4-methylbenzenesulfonate) as a solid Step 4: Into a 5 L 4 neckedround bottomed flask was placed a solution of 4-methylbenzene-1-sulfonylchloride (487 g, 2.55 mol) in ethyl ether (1 L). To the mixture wasadded a solution of ethane-1,2-diamine (77 g, 1.3 mol) and sodiumhydroxide (102 g, 2.55 mol) in H₂O (1 L) dropwise while cooled to 0° C.The resulting solution was allowed to stir for 30 min at 0° C. in an icebath, then overnight at room temperature. A filtration was performed andthe filter cake was washed 2 times with H₂O and dried in an oven. Thisresulted in (crude) N,N-ethane-1,2-diylbis(4-methylbenzenesulfonamide)as a solid.

Into a 5 L 4 necked round bottom flask were placedN,N-ethane-1,2-diylbis(4-methylbenzenesulfonamide) (150 g, 408 mmol),cyclopropane-1,1-diyldimethanediyl bis(4-methylbenzenesulfonate) (200 g,487 mmol), 18-crown-6 (53 g, 200 mmol) and THF (2 L) followed by theaddition of a solution of t-BuOK (100 g, 893 mmol) in THF (500 mL)dropwise with stirring at −30° C. The resulting solution was allowed tostir for 2 days at room temperature. The resulting mixture wasconcentrated under reduced pressure to remove most of THF. The residualsolution was diluted with 1500 mL of H₂O. The precipitate was collectedby filtration and dried. The residue was purified by eluting through asilica gel column with dichloromethane/petroleum ether (1:10-1:2). Thisresulted in 5,8-bis[(4-methylphenyl)sulfonyl]-5,8-diazaspiro[2.6]nonaneas a solid.

Step 5: Into a 5 L 4 necked round bottomed flask was placed a solutionof 5,8-bis[(4-methylphenyl)sulfonyl]-5,8-diazaspiro[2.6]nonane (100 g,230 mmol) in MeOH (1500 mL). To the mixture was added magnesium (27.4 g,1.14 mol) batchwise when the reaction mixture was warmed at 40° C. Theresulting mixture was allowed to stir for 2 h at room temperature. Theresulting mixture was concentrated under reduced pressure to removeMeOH. The residue was diluted with 500 mL of EtOAc and filtered. Thefiltrate was treated with a solution of oxalic acid (23 g, 255 mmol) inEt₂O (500 mL). The precipitate was collected by filtration and dried.This resulted in 5-[(4-methylphenyl)sulfonyl]-5,8-diazaspiro[2.6]nonaneethanedioate as a solid.

Step 6: Into a 2 L 3 necked round bottomed flask was placed a solutionof 5-[(4-methylphenyl)sulfonyl]-5,8-diazaspiro[2.6]nonane ethanedioate(50 g, 121.48 mmol, 90%) in DCM (800 mL) and Et₃N (31 g, 310 mmol). Tothe mixture was added Boc₂O (26 g, 119 mmol) at 0-5° C. The resultingsolution was allowed to stir overnight at room temperature. The reactionmixture was washed with 3×500 mL of H₂O and 1×500 mL of brine. Theorganic layer was dried over Na₂SO₄ and concentrated under reducedpressure. This resulted in tert-butyl8-[(4-methylphenyl)sulfonyl]-5,8-diazaspiro[2.6]nonane-5-carboxylate asan oil.

Step 7: Into a 3 L 3 necked round bottomed flask was placed a solutionof tert-butyl8-[(4-methylphenyl)sulfonyl]-5,8-diazaspiro[2.6]nonane-5-carboxylate(110 g, 232 mmol, 80%) in MeOH (1800 mL). To the mixture was added Mg(36 g, 1.50 mol) in several batches at 40° C. The resulting solution wasallowed to stir for 1 h at room temperature. The resulting mixture wasconcentrated under reduced pressure. The residue was diluted with 1 L ofEtOAc and filtered. The filtrate was treated with a solution of oxalicacid in ether to precipitate the product. The solid was collected byfiltration and washed 2 times with ether. This resulted in tert-butyl5,8-diazaspiro[2.6]nonane-5-carboxylate ethanedioate as a solid. ¹H-NMR(400 MHz, D₂O): δ 0.71-0.736 (d, J=9.6 Hz, 2H), 0.75-0.78 (d, J=9.6 Hz,2H), 0.77 (m, 4H), 1.42 (s, 9H), 3.18 (s, 2H), 3.33-3.39 (m, 4H), 3.78(s, 1H). MS [M+H]⁺ 227.

Example 1

2-{[(1R,2S)-2-Aminocyclohexyl]amino}-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide(IRAK4 IC₅₀=1 nM)

Step 1: Into a 25 mL round bottom flask containing a solution of2-chlorothieno[2,3-b]pyrazine-7-carboxylic acid (0.6 g, 2.8 mmol) inN,N-dimethylformamide (3 mL) were added N,N-diisopropylethylamine (1.7mL, 9.8 mmol),1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (1.6 g, 4.2 mmol) and1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-amine (0.55 g, 3.4 mmol) andthe reaction was stirred at room temperature for 16 h. The reactionmixture was treated with ice-cooled water (20 mL) and extracted withethyl acetate (3×50 mL). The combined organics were washed with brine(50 mL), dried over anhydrous sodium sulfate, filtered, concentratedunder reduced pressure and purified by flash chromatography (silica gel)eluting with 30-35% ethyl acetate in petroleum ether to afford2-chloro-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)thieno[2,3-b]pyrazine-7-carboxamideas a solid. ¹H NMR (CDCl₃, 300 MHz): δ 10.94 (brs, 1H), 8.96 (s, 1H),8.67 (s, 1H), 8.39 (s, 1H), 3.99 (s, 3H). MS calc'd [M−H]⁺360.0, found360.0.

Step 2: Into a 5 mL microwave vial charged with a solution of2-chloro-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)thieno[2,3-b]pyrazine-7-carboxamide(150 mg, 0.4 mmol) in ethanol (2 mL) were added tert-butyl((1S,2R)-2-aminocyclohexyl)carbamate (98 mg, 0.46 mmol) andN,N-diisopropylethylamine (0.15 mL, 0.83 mmol) and the reaction wasirradiated at 150° C. under microwave irradiation for 12 h. The reactionmixture was concentrated under reduced pressure and purified by flashchromatography (silica gel) eluting with 30% ethyl acetate in petroleumether to afford tert-butyl((1S,2R)-2-((7-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)carbamoyl)thieno[2,3-b]pyrazin-2-yl)amino)cyclohexyl)carbamateas a solid. MS calc'd [M+H]⁺ 540.2, found 540.0.

Step 3: Into a solution of tert-butyl((1S,2R)-2-((7-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)carbamoyl)thieno[2,3-b]pyrazin-2-yl)amino)cyclohexyl)carbamate(40 mg, 0.07 mmol) in dichloromethane (1 mL) was added trifluoroaceticacid (0.5 mL) and the reaction mixture was stirred at room temperaturefor 2 h. The reaction mixture was concentrated under reduced pressureand purified by preparative HPLC to afford2-(((1R,2S)-2-aminocyclohexyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)thieno[2,3-b]pyrazine-7-carboxamidetrifluoroacetate as a solid. ¹H NMR (CD₃OD, 400 MHz): δ 8.78 (s, 1H),8.35 (s, 1H), 8.25 (s, 1H), 4.78-4.77 (m, 1H), 4.00 (s, 3H), 3.56-3.54(m, 1H), 1.96-1.92 (m, 1H), 1.85-1.74 (m, 5H), 1.67-1.59 (m, 2H). MScalc'd [M+H]⁺ 440.1, found 440.2.

The following examples were prepared in an analogous manner of thatdescribed in Example 1.

Exact Example IRAK4 Mass # IC₅₀ (nM) Structure IUPAC Name [M + H]⁺  2 42

N-[1-methyl-3- (trifluoromethyl)-1H- pyrazol-4-yl]-2- piperazin-1-ylthieno[2,3-b] pyrazine-7- carboxamide trifluoroacetate Calc’d 412.1,found 412.2  3 100

2-{[(1R,2S)-2- hydroxycyclohexyl] amino}-N-[1-methyl-3-(trifluoromethyl)-1H- pyrazol-4-yl] thieno[2,3-b] pyrazine-7-carboxamide trifluoroacetate Calc’d 441.1, found 441.2  4 0.8

N-[1-methyl-3- (trifluoromethyl)-1H- pyrazol-4-yl]-2-[(3R)- piperazin-3-ylamino]thieno[2,3-b] pyrazine-7- carboxamide trifluoroacetate Calc’d426.1, found 426.2  5 332

2-{[(1R,2R)-2-amino- 3,3-difluorocyclohexyl] amino}-N-[1-methyl-3-(trifluoromethyl)-1H- pyrazol-4-yl] thieno[2,3-b] pyrazine-7-carboxamide trifluoroacetate Calc’d 476.1, found 476.2  6 17

2-(1,4-diazepan-1-yl)- N-[1-methyl-3- (trifluoromethyl)-1H-pyrazol-4-yl] thieno[2,3-b] pyrazine-7- carboxamide 426.1  7 109

2-(2,5- diazabicyclo[2.2.2]oct- 2-yl)-N-[1-methyl-3-(trifluoromethyl)-1H- pyrazol-4-yl] thieno[2,3-b] pyrazine-7-carboxamide Calc’d 438.1, found 438.4  8 18

2-(5,8- diazaspiro[2.6]non-5- yl)-N-[1-methyl-3- (trifluoromethyl)-1H-pyrazol-4-yl] thieno[2,3-b] pyrazine-7- carboxamide trifluoroacetateCalc’d 452.1, found 452.4  9 1

2-[(3R)-3- aminopiperidin-1-yl]- N-[1-methyl-3- (trifluoromethyl)-1H-pyrazol-4-yl] thieno[2,3-b] pyrazine-7- carboxamide trifluoroacetateCalc’d 426.1, found 426.1 10 30

N-[3-(difluoromethyl)- 1-methyl-1H-pyrazol- 4-yl]-2-{[(1R,2S)-2-hydroxycyclohexyl] amino}thieno[2,3-b] pyrazine-7- carboxamide Calc’d423.1, found 423.4 11 4

2-(2,5- diazabicyclo[2.2.2] oct-2-yl)-N-[3- (difluoromethyl)-1-methyl-1H-pyrazol-4- yl]thieno[2,3-b] pyrazine-7- carboxamide Calc’d420.1, found 420.4 12 3

N-[3-(difluoromethyl)- 1-methyl-1H-pyrazol- 4-yl]-2-piperazin-1-ylthieno[2,3-b] pyrazine-7- carboxamide trifluoroacetate Calc’d 394.1,found 394.2 13 6

2-(5,8- diazaspiro[2.6]non-5- yl)-N-[3- (difluoromethyl)-1-methyl-1H-pyrazol-4- yl]thieno[2,3-b] pyrazine-7- carboxamidetrifluoroacetate Calc’d 434.0, found 434.4 14 5

2-(1,4-diazepan-1-yl)- N-[3-(difluoromethyl)- 1-methyl-1H-pyrazol-4-yl]thieno[2,3-b] pyrazine-7- carboxamide trifluoroacetate Calc’d408.1, found 408.4 15 4

2-(azepan-3-ylamino)- N-[1-methyl-3 (trifluoromethyl)-1H- pyrazol-4-yl]thieno[2,3-b] pyrazine-7- carboxamide trifluoroacetate Calc’d 440.1,found 440.4 16 73

N-(3-chloro-1-methyl- 1H-pyrazol-4-yl)-2- [(1S,4S)- or (1R,4R)-2,5-diazabicyclo[2.2.2] oct-2-yl]thieno[2,3-b] pyrazine-7- carboxamidetrifluoroacetate Calc’d 404.1, found 404.4 17 15

N-(3-chloro-1-methyl- 1H-pyrazol-4-yl)-2- [(1S,4S)- or (1R,4R)-2,5-diazabicyclo[2.2.2] oct-2-yl]thieno[2,3-b] pyrazine-7- carboxamidetrifluoroacetate Calc’d 404.1, found 404.4 18 14

N-(3-chloro-1-methyl- 1H-pyrazol-4-yl)-2- (1,4-diazepan-1-yl)thieno[2,3-b] pyrazine-7- carboxamide trifluoroacetate Calc’d 392.0,found 392.4 19 70

N-(3-bromo-1-methyl- 1H-pyrazol-4-yl)-2- [(1S,4S)- or (1R,4R)-2,5-diazabicyclo[2.2.2] oct-2-yl]thieno[2,3-b] pyrazine-7- carboxamidetrifluoroacetate Calc’d 448.0, found 448.2 20 19

N-(3-bromo-1-methyl- 1H-pyrazol-4-yl)-2- [(1S,4S)- or (1R,4R)-2,5-diazabicyclo[2.2.2] oct-2-yl]thieno[2,3-b] pyrazine-7- carboxamidetrifluoroacetate Calc’d 448.0, found 448.4 21 15

N-(3-bromo-1-methyl- 1H-pyrazol-4-yl)-2- (1,4-diazepan-1-yl)thieno[2,3-b] pyrazine-7- carboxamide trifluoroacetate Calc’d 436.1,found 436.2 22 7

2-[(1S,4S)- or (1R,4R)- 2,5-diazabicyclo[2.2.2] oct-2-yl]-N-[3-(difluoromethyl)-1- methyl-1H-pyrazol-4- yl]thieno[2,3-b] pyrazine-7-carboxamide trifluoroacetate Calc’d 420.1, found 420.4 23 1

2-[(1S,4S)- or (1R,4R)- 2,5-diazabicyclo[2.2.2] oct-2-yl]-N-[3-(difluoromethyl)-1- methyl-1H-pyrazol-4- yl]thieno[2,3-b] pyrazine-7-carboxamide trifluoroacetate Calc’d 420.1, found 420.4 24 0.2

2[(3R)-3- aminopiperidin-1-yl] N-[3-(difluoromethyl)-1-methyl-1H-pyrazol- 4-yl]thieno[2,3-b] pyrazine-7- carboxamidetrifluoroacetate Calc’d 408.1, found 408.4 25 0.2

2-{[(1R,2S)-2- aminocyclohexyl]amino}- N-[3-(difluoromethyl)-1-methyl-1H-pyrazol- 4-yl]thieno[2,3-b] pyrazine-7- carboxamidetrifluoroacetate Calc’d 422.2, found 422.4 26 46

N-(3-cyano-1-methyl- 1H-pyrazol-4-yl)-2- [(1S,4S)- or (1R,4R)-2,5-diazabicyclo[2.2.2] oct-2-yl]thieno[2,3-b] pyrazine-7- carboxamidetrifluoroacetate Calc’d 395.1, found 395.4 27 37

N-(3-cyano-1-methyl- 1H-pyrazol-4-yl)-2- [(1S,4S)- or (1R,4R)-2,5-diazabicyclo[2.2.2] oct-2-yl]thieno[2,3-b] pyrazine-7- carboxamidetrifluoroacetate Calc’d 395.1, found 395.4 28 26

N-(3-cyano-1-methyl- 1H-pyrazol-4-yl)-2- (1,4-diazepan-1-yl)thieno[2,3-b] pyrazine-7- carboxamide trifluoroacetate Calc’d 383.1,found 383.4 29 107

2-{[(1R,2R)-2-amino- 3,3-difluorocyclohexyl] amino}-N- (3-(bromo-1-methyl-1H-pyrazol- 4-yl)thieno[2,3-b] pyrazine-7- carboxamidetrifluoroacetate Calc’d 486.1, found 486.2 30 0.6

2-{[(1R,2S)-2- aminocyclohexyl] amino}-N-(3-bromo-1- methyl-1H-pyrazol-4-yl)thieno[2,3-b] pyrazine-7- carboxamide trifluoroacetate Calc’d450.1, found 450.2 31 7

2-[(3S)- or (3R)- azepan-3-ylamino]-N- [1-methyl-3-(trifluoromethyl)-1H- pyrazol-4-yl] thieno[2,3-b] pyrazine-7-carboxamide trifluoroacetate Calc’d 440.1, found 440.2 32 0.4

N-[3-(difluoromethyl)- 1-methyl-1H-pyrazol- 4-yl]-2-[(3R)-piperidin-3-ylamino]thieno [2,3-b]pyrazine-7- carboxamide Calc’d 408.1, found408.2 33 0.2

2-[(3S)- or (3R)- azepan-3-ylamino]-N- [3-(difluoromethyl)-1-methyl-1H-pyrazol-4- yl]thieno[2,3-b] pyrazine-7- carboxamidetrifluoroacetate Calc’d 422.2, found 422.2 34 2

2-[(3S)- or (3R)- azepan-3-ylamino]-N- [3-(difluoromethyl)-1-methyl-1H-pyrazol-4- yl]thieno[2,3-b] pyrazine-7- carboxamidetrifluoroacetate Calc’d 422.2, found 422.4 35 0.3

2-{[(1R,2S)-2- aminocyclohexyl]amino}- N-(3-chloro-1- methyl-1H-pyrazol-4-yl)thieno[2,3-b] pyrazine-7- carboxamide trifluoroacetate Calc’d406.1, found 406.4 36 50

2-{[(1R,2R)-2-amino- 3,3-difluorocyclohexyl] amino}-N-(3-cyano-1-methyl-1H-pyrazol-4- yl]thieno[2,3-b] pyrazine-7- carboxamidetrifluoroacetate Calc’d 433.1, found 433.4 37 0.4

2-{[(1R,2S)-2- aminocyclohexyl]amino}- N-(3-cyano-1- methyl-1H-pyrazol-4-yl)thieno[2,3-b] pyrazine-7- carboxamide trifluoroacetate Calc’d397.2, found 397.4 38 0.6

2-[(3S)- or (3R)- azepan-3-ylamino]-N- [1-methyl-3- (trifluoromethyl)-1H-pyrazol-4- yl]thieno[2,3-b] pyrazine-7- carboxamide trifluoroacetateCalc’d 440.1, found 440.2 39 32

2-{[(1R,2R)-2-amino- 3,3-difluorocyclohexyl] amino}-N-[3-(difluoromethyl)-1- methyl-1H-pyrazol- 4-yl]thieno[2,3-b] pyrazine-7-carboxamide Calc’d 458.1, found 458.0 40 0.6

2-(3,8- diazabicyclo[3.2.1] oct-3-yl)-N-[3- (difluoromethyl)-1-methyl-1H-pyrazol-4- yl]thieno[2,3-b] pyrazine-7- carboxamidetrifluoroacetate Calc’d 420.1, found 420.4 41 18

2-(3,8- diazabicyclo[3.2.1]oct- 3-yl)-N-[1-methyl-3- (trifluoromethyl)-1H-pyrazol-4- yl]thieno[2,3-b] pyrazine-7- carboxamide trifluoroacetateCalc’d 438.1, found 438.4 42 16

2-{[(1R,2S)-2- aminocyclohexyl]amino}- N-(1-methyl-5-(trifluoromethyl)-1H- pyrazol-4- yl]thieno[2,3-b] pyrazine-7-carboxamide trifluoroacetate Calc’d 440.1, found 440.4 43 64

2-{[(1R,2R)-2-amino- 3,3-difluorocyclohexyl] amino}-N-(3-chloro-1-methyl-1H-pyrazol-4- yl)thieno[2,3-b] pyrazine-7- carboxamidetrifluoroacetate Calc’d 442.1, found 442.4 44 0.5

2-(3,8- diazabicyclo[3.2.1] oct-8-yl)-N-[3- (difluoromethyl)-1-methyl-1H-pyrazol-4- yl]thieno[2,3-b] pyrazine-7- carboxamidetrifluoroacetate Calc’d 420.1, found 420.4 45 2

2-(3,8- diazabicyclo[3.2.1]oct- 8-yl)-N-[1-methyl-3-(trifluoromethyl)-1H- pyrazol-4- yl]thieno[2,3-b] pyrazine-7-carboxamide trifluoroacetate Calc’d 438.1, found 438.4 46 812

N-(4-bromothiophen-3- yl)-2-[(1S,4S)- or (1R,4R)-2,5-diazabicyclo[2.2.2]oct- 2-yl]thieno[2,3-b] pyrazine-7- carboxamide 450.047 38

2-(1,4-diazepan-1-yl)- N-[4-(difluoromethyl) thiophen-3-yl]thieno[2,3-b] pyrazine-7- carboxamide trifluoroacetate Calc’d 410.1,found 410.4 48 346

N-(4-bromothiophen-3- yl)-2-(1,4-diazepan-1- yl)thieno[2,3-b]pyrazine-7- carboxamide trifluoroacetate Calc’d 438.1, found 438.2 49213

N-(4-bromothiophen-3- yl)-2-[(1S,4S)- or (1R,4R)-2,5-diazabicyclo[2.2.2]oct- 2-yl]thieno[2,3-b] pyrazine-7- carboxamidetrifluoroacetate Calc’d 450.0, found 450.2 50 0.7

2-{[(1R,2S)-2- aminocyclohexyl]amino}- N-(4-(difluoromethyl)thiophen-3-yl] thieno[2,3-b] pyrazine-7- carboxamide trifluoroacetateCalc’d 424.1, found 424.4 51 1161

N-(2-bromothiophen-3- yl)-2-(1,4-diazepan-1- yl)thieno[2,3-b]pyrazine-7- carboxamide trifluoroacetate Calc’d 438.1, found 438.2 52585

N-(2-chlorothiophen-3- yl)-2-(1,4-diazepan-1- yl)thieno[2,3-b]pyrazine-7- carboxamide trifluoroacetate Calc’d 394.1, found 394.4 530.6

2-{[(1R,2S)-2-amino- cyclohexyl]amino}- N-(4-bromothiophen-3-yl)thieno[2,3-b] pyrazine-7- carboxamide trifluoroacetate Calc’d452.0, found 452.0 54 1

2-{[(1R,2S)-2-amino- cyclohexyl]amino}- N-(2-bromothiophen-3-yl)thieno[2,3-b] pyrazine-7- carboxamide trifluoroacetate Calc’d452.0, found 452.2 55 189

N-(4-cyanothiophen-3- yl)-2-(1,4-diazepan-1- yl)thieno[2,3-b]pyrazine-7- carboxamide trifluoroacetate Calc’d 385.1, found 385.4 560.6

2-{[(1R,2S)-2-amino- cyclohexyl]amino}- N-(2-chlorothiophen-3-yl)thieno[2,3-b] pyrazine-7- carboxamide trifluoroacetate Calc’d408.1, found 408.2 57 0.5

2-{[(1R,2S)-2-amino- cyclohexyl]amino}- N-(4-cyanothiophen-3-yl)thieno[2,3-b] pyrazine-7- carboxamide trifluoroacetate Calc’d399.1, found 399.2 58 285

2-[(1S,4S)- or (1R,4R)- 2,5-diazabicyclo [2.2.2]oct-2-yl]-N-[4-(difluoromethyl) thiophen-3-yl] thieno[2,3-b] pyrazine-7- carboxamidetrifluoroacetate Calc’d 422.1, found 422.4 59 21

2-[(1S,4S)- or (1R,4R)- 2,5-diazabicyclo [2.2.2]oct-2-yl]-N-[4-(difluoromethyl) thiophen-3-yl] thieno[2,3-b] pyrazine-7- carboxamidetrifluoroacetate Calc’d 422.1, found 422.4 60 1413

2-{[(1R,2R)-2-amino- 3,3-difluorocyclohexyl] amino}-N-(2-chloro-thiophen-3-yl) thieno[2,3-b] pyrazine-7- carboxamide trifluoroacetateCalc’d 444.1, found 444.4 61 689

N-(2-chlorothiophen-3- yl)-2-[(1S,4S)- or (1R,4R)-2,5-diazabicylo[2.2.2]oct- 2-yl]thieno[2,3-b] pyrazine-7- carboxamidetrifluoroacetate Calc’d 406.1, found 406.4 62 274

N-(2-chlorothiophen-3- yl)-2-[(1S,4S)- or (1R,4R)-2,5-diazabicylo[2.2.2]oct- 2-yl]thieno[2,3-b] pyrazine-7- carboxamidetrifluoroacetate Calc’d 406.1, found 406.4 63 324

N-(2-bromothiophen-3- yl)-2-[(1S,4S)- or (1R,4R)-2,5-diazabicylo[2.2.2]oct- 2-yl]thieno[2,3-b] pyrazine-7- carboxamidetrifluoroacetate Calc’d 450.0, found 450.2 64 767

N-(2-bromothiophen-3- yl)-2-[(1S,4S)- or (1R,4R)-2,5-diazabicylo[2.2.2]oct- 2-yl]thieno[2,3-b] pyrazine-7- carboxamidetrifluoroacetate Calc’d 450.0, found 450.2 65 310

N-(4-cyanothiophen-3- yl)-2-[(1S,4S)- or (1R,4R)-2,5-diazabicylo[2.2.2]oct- 2-yl]thieno[2,3-b] pyrazine-7- carboxamideformate Calc’d 397.1, found 397.4 66 220

N-(4-cyanothiophen-3- yl)-2-[(1S,4S)- or (1R,4R)-2,5-diazabicylo[2.2.2]oct- 2-yl]thieno[2,3-b] pyrazine-7- carboxamideformate Calc’d 397.1, found 397.2 67 330

2-{[(1R,2R)-2-amino- 3,3-difluorocyclohexyl] amino}-N-[4-(difluoromethyl) thiophen-3-yl] thieno[2,3-b] pyrazine-7- carboxamidetrifluoroacetate Calc’d 460.1, found 460.4 68 2100

2-{[(1R,2R)-2-amino- 3,3-difluorocyclohexyl] amino}-N-(4-bromothiophen-3-yl) thieno[2,3-b] pyrazine-7- carboxamide formate Calc’d488.0, found 488.2 69 228

N-(2-cyanothiophen-3- yl)-2-[(1S,4S)- or (1R,4R)-2,5-diazabicyclo[2.2.2]oct- 2-yl]thieno[2,3-b] pyrazine-7- carboxamidetrifluoroacetate Calc’d 397.1, found 397.4 70 224

N-(2-cyanothiophen-3- yl)-2-[(1S,4S)- or (1R,4R)-2,5-diazabicyclo[2.2.2]oct- 2-yl]thieno[2,3-b] pyrazine-7- carboxamidetrifluoroacetate Calc’d 397.1, found 397.4 71 2069

2-{[(1R,2R)-2-amino- 3,3-difluorocyclohexyl] amino}-N-(2-bromothiophen-3-yl) thieno[2,3-b] pyrazine-7- carboxamidetrifluoroacetate Calc’d 488.0, found 488.2 72 422

N-(2-cyanothiophen-3- yl)-2-(1,4-diazepan-1- yl)thieno[2,3-b]pyrazine-7- carboxamide trifluoroacetate Calc’d 385.1, found 385.4 731587

2-(1,4-diazepan-1-yl)- N-[2-(trifluoromethyl) thiophen-3-yl]thieno[2,3-b] pyrazine-7- carboxamide trifluoroacetate Calc’d 428.1,found 428.2 74 3653

2-[(1S,4S)- or (1R,4R)- 2,5-diazabicyclo [2.2.2]oct-2-yl]-N-[2-(trifluoromethyl) thiophen-3-yl] thieno[2,3-b] pyrazine-7-carboxamide trifluoroacetate Calc’d 440.1, found 440.2 75 1231

2-[(1S,4S)- or (1R,4R)- 2,5-diazabicyclo [2.2.2]oct-2-yl]-N-[2-(trifluoromethyl) thiophen-3-yl] thieno[2,3-b] pyrazine-7-carboxamide trifluoroacetate Calc’d 440.1, found 440.2 76 12

2-{[(1R,2S)-2-amino- cyclohexyl]amino}- N-(2-(trifluoromethyl)thiophen-3-yl] thieno[2,3-b] pyrazine-7- carboxamide trifluoroacetateCalc’d 442.1, found 442.2 77 0.5

2-{[(1R,2S)-2-amino- cyclohexyl]amino}- N-(2-(cyanothiophen-3-yl)thieno[2,3-b] pyrazine-7- carboxamide trifluoroacetate Calc’d 399.1,found 399.o 78 3659

2-{[(1R,2R)-2-amino- 3,3-difluorocyclohexyl] amino}-N-(2-cyanothiophen-3-yl) thieno[2,3-b] pyrazine-7- carboxamidetrifluoroacetate Calc’d 435.1, found 435.2 79 371

2-{[(1R,2R)-2-amino- 3,3-difluorocyclohexyl] amino}-N-(4-cyanothiophen-3-yl) thieno[2,3-b] pyrazine-7- carboxamidetrifluoroacetate Calc’d 435.1, found 435.2

Example 80

N-(2-Cyanophenyl)-2-(1,4-diazepan-1-yl)thieno[2,3-b]pyrazine-7-carboxamide(IRAK4 IC₅₀=558 nM)

Step 1: Into a 25 mL round bottom flask containing a solution of2-chlorothieno[2,3-b]pyrazine-7-carboxylic acid (500 mg, 2.1 mmol) indichloromethane (10 mL) at 0° C. was added oxalyl chloride (0.5 mL, 11mmol) followed by N,N-dimethylformamide (1 drop) and the reaction wasstirred at room temperature for 1 h. The reaction mixture wasconcentrated to afford 2-chlorothieno[2,3-b]pyrazine-7-carbonylchloride, which was taken to the next step without further purification.

Into a 10 mL round bottom flask charged with 2-aminobenzonitrile (0.38g, 3.2 mmol) and N,N-diisopropylethylamine (0.5 mL, 6.4 mmol) indichloromethane (3 mL) at 0° C. was added2-chlorothieno[2,3-b]pyrazine-7-carbonyl chloride in dichloromethane (2mL) dropwise and the reaction mixture was stirred at room temperaturefor 3 h. The reaction mixture was treated with ice cold water (4 mL) andextracted with dichloromethane (3×10 mL). The combined organics werewashed with brine (20 mL) and dried over anhydrous sodium sulfate. Thesolution was filtered, concentrated under reduced pressure and purifiedby flash chromatography (silica gel) eluting with 20-30% ethyl acetatein petroleum ether to afford2-chloro-N-(2-cyanophenyl)thieno[2,3-b]pyrazine-7-carboxamide as asolid. ¹H NMR (CD₃OD, 400 MHz): δ 9.22 (s, 1H), 8.81 (s, 1H), 7.83-7.73(m, 3H), 7.38 (t, J=7.6 Hz, 1H). MS calc'd [M+H]⁺ 315.0, found 315.4.

Step 2: Into a 10 mL Pyrex tube containing a solution of2-chloro-N-(2-cyanophenyl)thieno[2,3-b]pyrazine-7-carboxamide (50 mg,0.15 mmol) in ethanol (2 mL) was added tert-butyl1,4-diazepane-1-carboxylate (38 mg, 0.19 mmol) followed byN,N-diisopropylethylamine (0.1 mL, 0.48 mmol) and the reaction washeated at 140° C. for 16 h. The reaction mixture was cooled to roomtemperature, concentrated under reduced pressure and purified by flashchromatography (silica gel) eluting with 30-40% ethyl acetate inpetroleum ether to afford tert-butyl4-(7-((2-cyanophenyl)carbamoyl)thieno[2,3-b]pyrazin-2-yl)-1,4-diazepane-1-carboxylateas a liquid. MS calc'd [M+H]⁺ 479.2, found 479.2.

Step 3: To a stirred solution of tert-butyl4-(7-((2-cyanophenyl)carbamoyl)thieno[2,3-b]pyrazin-2-yl)-1,4-diazepane-1-carboxylate(50 mg, 0.1 mmol) in dichloromethane (3 mL) was added trifluoroaceticacid (0.3 mL) and the reaction mixture was stirred at room temperaturefor 2 h. The reaction mixture was concentrated under reduced pressureand purified by preparative HPLC to affordN-(2-cyanophenyl)-2-(1,4-diazepan-1-yl)thieno[2,3-b]pyrazine-7-carboxamidetrifluoroacetate as a solid. ¹H NMR (CD₃OD, 400 MHz): δ 8.93 (s, 1H),8.46 (s, 1H), 8.10 (d, J=8.0 Hz, 1H), 7.83-7.74 (m, 2H), 7.40 (t, J=6.8Hz, 1H), 4.27 (t, J=5.2 Hz, 2H), 4.04 (t, J=6.0 Hz, 2H), 3.55 (t, J=5.6Hz, 2H), 3.38 (t, J=5.2 Hz, 2H), 2.30-2.25 (m, 2H). MS calc'd [M+H]⁺379.1, found 379.4.

The following examples were prepared in an analogous manner of thatdescribed in Example 80.

Example IRAK4 Exact Mass # IC₅₀ (nM) Structure IUPAC Name [M + H]⁺ 81 86

2-{[(1R,2S)-2- aminocyclo- hexyl]amino}- N-[2- (trifluoromethyl)phenyl]thieno[2, 3-b]pyrazine-7- carboxamide trifluoroacetate Calc'd436.1, found 435.8 82 2338

N-(2- bromophenyl)- 2-(1,4-diazepan- 1-yl)thieno[2,3- b]pyrazine-7-carboxamide trifluoroacetate Calc'd 432.0, found 432.2 83 899

N-(2- cyanophenyl)-2- (5,8-diazaspiro- [2.6]non-5-yl)- thieno[2,3-b]-pyrazine-7- carboxamide trifluoroacetate Calc'd 405.1, found 405.4 84 33

2-[(3R)-3- aminopiperidin- 1-yl]-N-(2- cyanophenyl)- thieno[2,3-b]-pyrazine-7- carboxamide trifluoroacetate Calc'd 379.1, found 379.4 85 2

N-(2- cyanophenyl)-2- [(3R)-piperidin- 3-ylamino]- thieno[2,3-b]-pyrazine-7- carboxamide trifluoroacetate Calc'd 379.1, found 379.4 86292

N-(2- cyanophenyl)-2- piperazin-1-yl- thieno[2,3-b]- pyrazine-7-carboxamide trifluoroacetate Calc'd 365.1, found 365.4 87 2

2-{[(1R,2S)-2- aminocyclohexyl]- amino}-N-(2- bromophenyl)-thieno[2,3-b]- pyrazine-7- carboxamide trifluoroacetate Calc'd 446.1,found 446.4 88 2872

N-(2- bromophenyl)- 2-[(1S,4S)- or (1R,4R)-2,5- diazabicyclo-[2.2.2]oct-2- yl]thieno[2,3-b]- pyrazine-7- carboxamide trifluoroacetateCalc'd 444.1, found 444.2 89 612

N-(2- bromophenyl)- 2-[(1S,4S)- or (1R,4R)-2,5- diazabicyclo-[2.2.2]oct-2- yl]thieno[2,3-b]- pyrazine-7- carboxamide trifluoroacetateCalc'd 444.1, found 444.2 90 6395

2-(1,4-diazepan- 1-yl)-N-[2- (trifluoromethyl) phenyl]thieno[2,3-b]pyrazine-7- carboxamide trifluoroacetate Calc'd 422.1, found 422.491 595

N-(2- chlorophenyl)-2- (1,4-diazepan-1- yl)thieno[2,3-b]- pyrazine-7-carboxamide trifluoroacetate Calc'd 388.1, found 388.4 92 0.8

2-{(1R,2S)-2- aminocyclohexyl]- amino}-N-(2- chlorophenyl)-thieno[2,3-b]- pyrazine-7- carboxamide trifluoroacetate Calc'd 402.1,found 402.4 93 4

2-[(3S)- or (3R)- azepan-3- ylamino]-N-(2- cyanophenyl)- thieno[2,3-b]-pyrazine-7- carboxamide trifluoroacetate Calc'd 393.1, found 393.4 94 9

2-[(3S)- or (3R)- azepan-3- ylamino]-N-(2- cyanophenyl)- thieno[2,3-b]-pyrazine-7- carboxamide trifluoroacetate Calc'd 393.1, found 393.4 950.5

2-{[(1R,2S)-2- aminocyclohexyl]- amino}-N-(2- cyanophenyl)-thieno[2,3-b]- pyrazine-7- carboxamide trifluoroacetate Calc'd 393.1,found 393.4 96 2011

2-{[(1R,2R)- 2-amino-3,3- difluorocyclo- hexyl]amino}- N-(2-bromo-phenyl)thieno- [2,3-b]- pyrazine-7- carboxamide Calc'd 482.0, found482.0 97 173

N-(2- cyanophenyl)-2- [(1S,4S)- or (1R,4R)-2,5- diazabicyclo-[2.2.2]oct-2- yl]thieno[2,3-b]- pyrazine-7- carboxamide trifluoroacetateCalc'd 391.1, found 391.4 98 251

N-(2- cyanophenyl)-2- [(1S,4S)- or (1R,4R)-2,5- diazabicyclo-[2.2.2]oct-2- yl]thieno[2,3-b]- pyrazine-7- carboxamide trifluoroacetateCalc'd 391.1, found 391.4 99 1556

N-(2- chlorophenyl)-2- [(1S,4S)- or (1R,4R)-2,5- diazabicyclo-[2.2.2]oct-2- yl]thieno[2,3-b]- pyrazine-7- carboxamide trifluoroacetateCalc'd 400.1, found 400.4 100 191

N-(2- chlorophenyl)-2- [(1S,4S)- or (1R,4R)-2,5- diazabicyclo-[2.2.2]oct-2- yl]thieno[2,3-b]- pyrazine-7- carboxamide trifluoroacetateCalc'd 400.1, found 400.4 101 545

2-{[(1R,2R)-2- amino-3,3- difluorocyclohexyl]- amino}-N-(2-chlorophenyl)- thieno[2,3-b]- pyrazine-7- carboxamide trifluoroacetateCalc'd 438.1, found 438.4 102 25

2-{[(1R,2S)-2- aminocyclohexyl]- amino}-N-[2- (difluoromethyl)phenyl]thieno- [2,3-b]- pyrazine-7- carboxamide trifluoroacetate Calc'd418.2, found 418.4 103 3630

2-(1,4-diazepan- 1-yl)-N-[2- (difluoromethyl) phenyl]thieno[2,3-b]pyrazine-7- carboxamide trifluoroacetate Calc'd 404.1, found 404.4104 4180

2-[(1S,4S)- or (1R,4R)-2,5- diazabicyclo- [2.2.2]oct-2-yl]-N-[2-(difluoro- methyl)phenyl]- thieno[2,3-b]- pyrazine-7- carboxamidetrifluoroacetate Calc'd 416.1, found 416.2 105 146

2-{[(1R,2R)-2- amino-3,3- difluorocyclohexyl]- amino}-N-(2-cyanophenyl)- thieno[2,3-b]- pyrazine-7- carboxamide trifluoroacetateCalc'd 429.1, found 429.4 106 2583

2-{[(1R,2R)-2- amino-3,3- difluorocyclohexyl]- amino}-N-[2-(difluoromethyl) phenyl]thieno[2, 3-b]pyrazine-7- carboxamidetrifluoroacetate Calc'd 454.1, found 454.4 107 151

N-(4- chlorothiophen- 3-yl)-2-(1,4- diazepan-1-yl)- thieno[2,3-b]-pyrazine-7- carboxamide trifluoroacetate Calc'd 394.1, found 394.2 108307

N-(4- chlorothiophen- 3-yl)-2-[(1S,4S)- or (1R,4R)-2,5- diazabicyclo-[2.2.2]oct-2-yl]- thieno[2,3-b]- pyrazine-7- carboxamidetrifluoroacetate Calc'd 406.1, found 406.2 109 104

N-(4- chlorothiophen- 3-yl)-2-[(1S,4S)- or (1R,4R)-2,5- diazabicyclo-[2.2.2]oct-2-yl]- thieno[2,3-b]- pyrazine-7- carboxamidetrifluoroacetate Calc'd 406.1, found 406.2 110 0.7

2-{[(1R,2S)-2- aminocyclohexyl]- amino}-N-(4- chlorothiophen-3-yl)thieno[2,3-b]- pyrazine-7- carboxamide trifluoroacetate Calc'd408.1, found 408.2 111 645

2-{[(1R,2R)-2- amino-3,3- difluorocyclohexyl]- amino}-N-(4-chlorothiophen- 3-yl)thieno[2,3-b]- pyrazine-7- carboxamidetrifluoroacetate Calc'd 444.1, found 444.2

Biological Data

Compounds of the instant invention were tested by the assay describedbelow and were found to have IRAK4 inhibitory activity. Data is shown inthe representative table(s). Other assays are known in the literatureand could be readily performed by those of skill in the art.

IRAK4 Kinase Assay

The kinase activity of IRAK4 is determined by its ability to catalyzethe phosphorylation of a fluorescent polypeptide substrate. The extentof phosphorylation is measured using the IMAP technology (MolecularDevices) where the phosphorylated fluorescent substrate binds to thelarge M(III)-based nanoparticles which reduces the rotational speed ofthe substrate and thus increases its fluorescent polarization (FP).

20 μL reaction mixture contains 10 mM TriHCl, pH 7.2, 0.5 nM GST taggedIRAK4 (SignalChem), 100 nM fluorescent peptide substrate (RP7030,Molecular Devices), 100 μM ATP, 1 mM DDT, 1 mM MgCl₂, and 0.01% Tween20. The reaction is initiated by the addition of ATP. After incubationfor 30 minutes at 25° C., 60 μL of Progressive IMAP Reagent (MolecularDevices) is added to stop the reaction. Change in RP7030's FP isdetermined by a FP reader (Analyst HT, LJL BioSystems).

What is claimed is:
 1. A compound according to Formula I:

wherein: Ring A is aryl or heterocyclyl; n is 0, 1, 2, 3 or 4; R₁ isindependently selected from: (C₁-C₄)alkyl, (C₃-C₆)cycloalkyl,heterocyclyl, CF₃, CHF₂, CN, halo, said alkyl, cycloalkyl andheterocyclyl optionally substituted with halo, OH, CH₃, and OCH₃; R₂ isH and R₃ is independently selected from: (C₁-C₆)alkyl, (C₃-C₈)cycloalkyland heterocyclyl each optionally substituted with one or more halo, OH,N(R_(b))₂, or morpholinyl, or R₂ and R₃ can be taken together with thenitrogen to which they are attached to form a heterocyclyl, saidheterocyclyl optionally substituted with one or more substituentsselected from R_(a); R_(a) is independently selected from (C₁-C₄)alkyl,(C₃-C₆)cycloalkyl, CF₃, CHF₂, OH, halo and NH₂, said alkyl optionallysubstituted with (C₃-C₆)cycloalkyl and CF₃; and R_(b) is independentlyselected from H and (C₁-C₄)alkyl; or a pharmaceutically acceptable saltthereof.
 2. A compound according to claim 1 of Formula I: wherein: RingA is pyrazolyl, pyridinyl, thiophenyl, furanyl or phenyl; n is 0, 1 or2; R₁ is independently selected from: (C₁-C₄)alkyl, cyclopropyl,oxadiazolyl, pyridinyl, oxazolyl, triazolyl, pyriminidyl, CF₃, CHF₂, CNand halo, said alkyl, oxadiazolyl, pyridinyl, oxazolyl, triazolyl andpyriminidyl are optionally substituted with halo, OH, CH₃, and OCH₃; R₂is H and R₃ is independently selected from: (C₁-C₄)alkyl, cyclohexyl,cycloheptyl, piperidinyl and azepanyl each optionally substituted withone or more F, OH, N(R_(b))₂, or morpholinyl, or R₂ and R₃ can be takentogether with the nitrogen to which they are attached to form aheterocyclyl selected from piperazinyl, diazepanyl, diazabicyclooctyl,diazabicycloheptyl, diazaspirononyl, hexahydropyrrolopyrazinyl,piperidinyl, diazabicyclononyl, oxadiazabicyclodecyl anddiazatricyclodecyl, said heterocyclyl optionally substituted with one ormore substituents selected from R_(a); R_(a) is independently selectedfrom (C₁-C₄)alkyl, cyclopropyl, CF₃, CHF₂, OH, F and NH₂, said alkyloptionally substituted with cyclopropyl and CF₃; and R_(b) isindependently selected from H and methyl; or a pharmaceuticallyacceptable salt thereof.
 3. A compound which is selected from:2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-piperazin-1-ylthieno[2,3-b]pyrazine-7-carboxamide;2-{[(1R,2S)-2-hydroxycyclohexyl]amino}-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-[(3R)-piperidin-3-ylamino]thieno[2,3-b]pyrazine-7-carboxamide;2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;2-(1,4-diazepan-1-yl)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;2-(2,5-diazabicyclo[2.2.2]oct-2-yl)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;2-(5,8-diazaspiro[2.6]non-5-yl)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;2-[(3R)-3-aminopiperidin-1-yl]-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]-2-{[(1R,2S)-2-hydroxycyclohexyl]amino}thieno[2,3-b]pyrazine-7-carboxamide;2-(2,5-diazabicyclo[2.2.2]oct-2-yl)-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]-2-piperazin-1-ylthieno[2,3-b]pyrazine-7-carboxamide;2-(5,8-diazaspiro[2.6]non-5-yl)-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;2-(1,4-diazepan-1-yl)-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;2-(azepan-3-ylamino)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;N-(3-chloro-1-methyl-1H-pyrazol-4-yl)-2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;N-(3-chloro-1-methyl-1H-pyrazol-4-yl)-2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;N-(3-chloro-1-methyl-1H-pyrazol-4-yl)-2-(1,4-diazepan-1-yl)thieno[2,3-b]pyrazine-7-carboxamide;N-(3-bromo-1-methyl-1H-pyrazol-4-yl)-2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;N-(3-bromo-1-methyl-1H-pyrazol-4-yl)-2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;N-(3-bromo-1-methyl-1H-pyrazol-4-yl)-2-(1,4-diazepan-1-yl)thieno[2,3-b]pyrazine-7-carboxamide;2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;2-[(3R)-3-aminopiperidin-1-yl]-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;N-(3-cyano-1-methyl-1H-pyrazol-4-yl)-2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;N-(3-cyano-1-methyl-1H-pyrazol-4-yl)-2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;N-(3-cyano-1-methyl-1H-pyrazol-4-yl)-2-(1,4-diazepan-1-yl)thieno[2,3-b]pyrazine-7-carboxamide;2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-(3-bromo-1-methyl-1H-pyrazol-4-yl)thieno[2,3-b]pyrazine-7-carboxamide;2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(3-bromo-1-methyl-1H-pyrazol-4-yl)thieno[2,3-b]pyrazine-7-carboxamide;2-[(3S)-azepan-3-ylamino]-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]-2-[(3R)-piperidin-3-ylamino]thieno[2,3-b]pyrazine-7-carboxamide;2-[(3R)-azepan-3-ylamino]-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;2-[(3S)-azepan-3-ylamino]-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(3-chloro-1-methyl-1H-pyrazol-4-yl)thieno[2,3-b]pyrazine-7-carboxamide;2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-(3-cyano-1-methyl-1H-pyrazol-4-yl)thieno[2,3-b]pyrazine-7-carboxamide;2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(3-cyano-1-methyl-1H-pyrazol-4-yl)thieno[2,3-b]pyrazine-7-carboxamide;2-[(3R)-azepan-3-ylamino]-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;2-(3,8-diazabicyclo[3.2.1]oct-3-yl)-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;2-(3,8-diazabicyclo[3.2.1]oct-3-yl)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-(3-chloro-1-methyl-1H-pyrazol-4-yl)thieno[2,3-b]pyrazine-7-carboxamide;2-(3,8-diazabicyclo[3.2.1]oct-8-yl)-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;2-(3,8-diazabicyclo[3.2.1]oct-8-yl)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide;N-(4-bromothiophen-3-yl)-2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;2-(1,4-diazepan-1-yl)-N-[4-(difluoromethyl)thiophen-3-yl]thieno[2,3-b]pyrazine-7-carboxamide;N-(4-bromothiophen-3-yl)-2-(1,4-diazepan-1-yl)thieno[2,3-b]pyrazine-7-carboxamide;N-(4-bromothiophen-3-yl)-2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-[4-(difluoromethyl)thiophen-3-yl]thieno[2,3-b]pyrazine-7-carboxamide;N-(2-bromothiophen-3-yl)-2-(1,4-diazepan-1-yl)thieno[2,3-b]pyrazine-7-carboxamide;N-(2-chlorothiophen-3-yl)-2-(1,4-diazepan-1-yl)thieno[2,3-b]pyrazine-7-carboxamide;2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(4-bromothiophen-3-yl)thieno[2,3-b]pyrazine-7-carboxamide;2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(2-bromothiophen-3-yl)thieno[2,3-b]pyrazine-7-carboxamide;N-(4-cyanothiophen-3-yl)-2-(1,4-diazepan-1-yl)thieno[2,3-b]pyrazine-7-carboxamide;2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(2-chlorothiophen-3-yl)thieno[2,3-b]pyrazine-7-carboxamide;2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(4-cyanothiophen-3-yl)thieno[2,3-b]pyrazine-7-carboxamide;2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]-N-[4-(difluoromethyl)thiophen-3-yl]thieno[2,3-b]pyrazine-7-carboxamide;2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]-N-[4-(difluoromethyl)thiophen-3-yl]thieno[2,3-b]pyrazine-7-carboxamide;2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-(2-chlorothiophen-3-yl)thieno[2,3-b]pyrazine-7-carboxamide;N-(2-chlorothiophen-3-yl)-2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;N-(2-chlorothiophen-3-yl)-2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;N-(2-bromothiophen-3-yl)-2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;N-(2-bromothiophen-3-yl)-2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;N-(4-cyanothiophen-3-yl)-2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;N-(4-cyanothiophen-3-yl)-2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-[4-(difluoromethyl)thiophen-3-yl]thieno[2,3-b]pyrazine-7-carboxamide;2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-(4-bromothiophen-3-yl)thieno[2,3-b]pyrazine-7-carboxamide;N-(2-cyanothiophen-3-yl)-2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;N-(2-cyanothiophen-3-yl)-2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-(2-bromothiophen-3-yl)thieno[2,3-b]pyrazine-7-carboxamide;N-(2-cyanothiophen-3-yl)-2-(1,4-diazepan-1-yl)thieno[2,3-b]pyrazine-7-carboxamide;2-(1,4-diazepan-1-yl)-N-[2-(trifluoromethyl)thiophen-3-yl]thieno[2,3-b]pyrazine-7-carboxamide;2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]-N-[2-(trifluoromethyl)thiophen-3-yl]thieno[2,3-b]pyrazine-7-carboxamide;2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]-N-[2-(trifluoromethyl)thiophen-3-yl]thieno[2,3-b]pyrazine-7-carboxamide;2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-[2-(trifluoromethyl)thiophen-3-yl]thieno[2,3-b]pyrazine-7-carboxamide;2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(2-cyanothiophen-3-yl)thieno[2,3-b]pyrazine-7-carboxamide;2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-(2-cyanothiophen-3-yl)thieno[2,3-b]pyrazine-7-carboxamide;2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-(4-cyanothiophen-3-yl)thieno[2,3-b]pyrazine-7-carboxamide;N-(2-cyanophenyl)-2-(1,4-diazepan-1-yl)thieno[2,3-b]pyrazine-7-carboxamide;2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-[2-(trifluoromethyl)phenyl]thieno[2,3-b]pyrazine-7-carboxamide;N-(2-bromophenyl)-2-(1,4-diazepan-1-yl)thieno[2,3-b]pyrazine-7-carboxamide;N-(2-cyanophenyl)-2-(5,8-diazaspiro[2.6]non-5-yl)thieno[2,3-b]pyrazine-7-carboxamide;2-[(3R)-3-aminopiperidin-1-yl]-N-(2-cyanophenyl)thieno[2,3-b]pyrazine-7-carboxamide;N-(2-cyanophenyl)-2-[(3R)-piperidin-3-ylamino]thieno[2,3-b]pyrazine-7-carboxamide;N-(2-cyanophenyl)-2-piperazin-1-ylthieno[2,3-b]pyrazine-7-carboxamide;2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(2-bromophenyl)thieno[2,3-b]pyrazine-7-carboxamide;N-(2-bromophenyl)-2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;N-(2-bromophenyl)-2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;2-(1,4-diazepan-1-yl)-N-[2-(trifluoromethyl)phenyl]thieno[2,3-b]pyrazine-7-carboxamide;N-(2-chlorophenyl)-2-(1,4-diazepan-1-yl)thieno[2,3-b]pyrazine-7-carboxamide;2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(2-chlorophenyl)thieno[2,3-b]pyrazine-7-carboxamide;2-[(3S)-azepan-3-ylamino]-N-(2-cyanophenyl)thieno[2,3-b]pyrazine-7-carboxamide;2-[(3R)-azepan-3-ylamino]-N-(2-cyanophenyl)thieno[2,3-b]pyrazine-7-carboxamide;2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(2-cyanophenyl)thieno[2,3-b]pyrazine-7-carboxamide;2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-(2-bromophenyl)thieno[2,3-b]pyrazine-7-carboxamide;N-(2-cyanophenyl)-2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;N-(2-cyanophenyl)-2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;N-(2-chlorophenyl)-2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;N-(2-chlorophenyl)-2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-(2-chlorophenyl)thieno[2,3-b]pyrazine-7-carboxamide;2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-[2-(difluoromethyl)phenyl]thieno[2,3-b]pyrazine-7-carboxamide;2-(1,4-diazepan-1-yl)-N-[2-(difluoromethyl)phenyl]thieno[2,3-b]pyrazine-7-carboxamide;2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]-N-[2-(difluoromethyl)phenyl]thieno[2,3-b]pyrazine-7-carboxamide;2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-(2-cyanophenyl)thieno[2,3-b]pyrazine-7-carboxamide;2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-[2-(difluoromethyl)phenyl]thieno[2,3-b]pyrazine-7-carboxamide;N-(4-chlorothiophen-3-yl)-2-(1,4-diazepan-1-yl)thieno[2,3-b]pyrazine-7-carboxamide;N-(4-chlorothiophen-3-yl)-2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;N-(4-chlorothiophen-3-yl)-2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]thieno[2,3-b]pyrazine-7-carboxamide;2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(4-chlorothiophen-3-yl)thieno[2,3-b]pyrazine-7-carboxamide;and2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-(4-chlorothiophen-3-yl)thieno[2,3-b]pyrazine-7-carboxamide;or a pharmaceutically acceptable salt thereof.
 4. A pharmaceuticalcomposition comprising a pharmaceutical carrier and a therapeuticallyeffective amount of a compound of claim
 1. 5. The use of the compoundaccording to claim 1 for the preparation of a medicament useful in thetreatment or prevention of an inflammation related disease in a mammalin need of such treatment.
 6. A compound of claim 1 for use in therapy.7. A method for treating an inflammatory disease which comprisesadministering to a mammal in need thereof a therapeutically effectiveamount of a compound of claim 1 or a pharmaceutically acceptable saltthereof.
 8. The method according to claim 7 wherein the inflammatorydisease is selected from rheumatoid arthritis, inflammatory boweldisease and cancer.
 9. A method of treating an inflammatory diseasewhich comprises administering a therapeutically effective amount of acompound of claim 1, or a pharmaceutically acceptable salt thereof, incombination with a second therapeutic agent.
 10. The method of claim 9wherein the second therapeutic agent is selected from an anti-canceragent and an anti-inflammatory agent.